Search

Long-term stress is a significant risk factor for cardiovascular diseases, including atherosclerosis and endothelial dysfunction. Moreover, prolonged stress has shown to negatively regulate central BDNF expression. The role of central BDNF in CNS disorders is well studied until recently the peripheral BDNF was also found to be involved in endothelial function regulation and atherosclerosis. The peripheral BDNF and its role in chronic stress-induced atherosclerosis and endothelial dysfunction remain unclear. Therefore, we aimed to elucidate the role of BDNF and its modulation by the HDAC inhibitor valproic acid (VA) in chronic unpredictable stress (CUS)-induced atherosclerosis and endothelial dysfunction. We demonstrated that a 10-week CUS mouse model substantially decreases central and peripheral BDNF expression, resulting in enhanced serum lipid indices, plaque deposition, fibrosis, and CD68 expression in thoracic aortas. Further, parameters associated with endothelial dysfunction such as increased levels of endothelin-1 (ET-1), adhesion molecules like VCAM-1, M1 macrophage markers, and decreased M2 macrophage markers, eNOS expression, and nitrite levels in aortas, were also observed. VA (50 mg/kg, 14 days, i. p.) was administered to mice following 8 weeks of CUS exposure until the end of the experimental procedure. VA significantly prevented the decrease in BDNF, eNOS and nitrite levels, reduced lesion formation and fibrosis in thoracic aortas and increased ET-1, and VCAM-1 followed by M2 polarization in VA-treated mice. The study highlights the potential of epigenetic modulation of BDNF as a therapeutic target, in stress-induced cardiovascular pathologies and suggests that VA could be a promising agent for mitigating CUS-induced endothelial dysfunction and atherosclerosis by BDNF modulation., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Diabetic macular edema (DME) is the primary cause of vision impairment in diabetic retinopathy (DR) patients. A previous study has shown the efficacy of montelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, in a diabetic mouse model. This study aims to understand the CysLTR1 signaling in retinal endothelial cells and the impact of montelukast., Methods: Primary human retinal microvascular endothelial cells (HRECs) challenged with 20 ng/mL TNF-α and 30 mM D-glucose (D-glu) for six to 24 hours served as a model of endothelial activation. HRECs were incubated with L-glucose (L-glu) as an osmotic control. CysLTR1 knockdown and montelukast pretreatment assessed CysLTR1 antagonism. Gene expression, protein expression, and cell-permeable dyes were utilized to measure autophagy and inflammation. Transendothelial electrical resistance (TER) and transendothelial migration of mononuclear leukocytes across HRECs monolayer were measured as a functional assessment of vascular permeability., Results: Endothelial activation induced by hyperglycemia and inflammation increased CysLTR1 expression, triggering autophagy within two to six hours, IL-1β production, loss of junction integrity, decreased TER, and increased leukocyte migration within six to 24 hours. Pretreatment with montelukast effectively alleviated these effects, demonstrating its dependence on CysLTR1., Conclusions: Dysfunctional retinal endothelium initiates a self-reinforcing loop of inflammation, autophagy, and compromised integrity associated with heightened CysLTR1 levels. The antagonistic effect of montelukast against CysLTR1 effectively mitigates these detrimental changes. This study reveals CysLTR1 as a potential therapeutic target in treating DME and offers a novel strategy to mitigate detrimental changes in DR.

Alarmins are classified by their release from damaged or ruptured cells. Many alarmins have been found to increase vascular tone and oppose endothelium-dependent dilatation (EDD). Interleukin (IL)-33 plays a prominent role in lung injury and can be released during vascular injury and in chronic studies found to be cardioprotective. Our recent work has implicated IL-33 in acute vascular dysfunction following inhalation of engineered nanomaterials (ENM). However, the mechanisms linking IL-33 to vascular tone have not been interrogated. We therefore aimed to determine whether IL-33 directly influenced microvascular tone and endothelial function. Isolated feed arteries and in vivo arterioles from male and female Sprague-Dawley rats were used to determine direct vascular actions of IL-33. Mesenteric feed arteries and arterioles demonstrated reduced intraluminal diameters when treated with increasing concentrations of recombinant IL-33. IL-33 activated extracellular signal regulated kinase (ERK)1/2 of rat aortic smooth muscle cells but not phosphorylation of myosin light chain kinase. This suggested IL-33 may sensitize arterioles to Ca 2+ -mediated responses. Indeed, IL-33 augmented the myogenic- and phenylephrine-induced vasoconstriction. Additionally, incubation of arterioles with 1 ng IL-33 attenuated ACh-mediated EDD. Mechanistically, in human aortic endothelial cells, we demonstrate that IL-33-mediated ERK1/2 activation leads to inhibitory phosphorylation of serine 602 on endothelial nitric oxide synthase. Finally, we demonstrate that IL-33-ERK1/2 contributes to vascular tone following two known inducers of IL-33; ENM inhalation and the rupture endothelial cells. The present study provides novel evidence that IL-33 increases vascular tone via canonical ERK1/2 activation in microvascular smooth muscle and endothelium. Altogether, it is suggested IL-33 plays a critical role in microvascular homeostasis following barrier cell injury. KEY POINTS: Interleukin (IL)-33 causes a concentration-dependent reduction in feed artery diameter. IL-33 acts on vascular smooth muscle cells to augment Ca 2+ -mediated processes. IL-33 causes inhibitory phosphorylation of endothelial nitric oxide synthase and opposes endothelium-dependent dilatation. Engineered nanomaterial-induced lung injury and endothelial cell rupture in part act through IL-33 to mediate increased vascular tone., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Aim: Preeclampsia is a complex and serious pregnancy disorder that leads to maternal and neonatal mortality worldwide. Kefir peptides (KPs), derived from various prebiotic fermentations in whole milk by kefir grains, were investigated for their potential therapeutic effects. In this study, we used the L-NAME in drinking water to induce a preeclampsia-like condition in spontaneous hypertension stroke-prone (SHRSP) pregnant rats., Main Methods: The rats were assigned to five groups: the normal group (WKY rats), the untreated group (SHRSP rat control pregnant), the L-NAME/Mock group (SHRSP rats fed with L-NAME water), the L-NAME/KPs-LD group (SHRSP rats fed with L-NAME water and low-dose KPs diets), and the L-NAME/KPs-HD group (SHRSP rats fed with L-NAME water and high-dose KPs diets) for a 20-day experiment. Chorioallantois membrane (CAM) assay was applied for ex vivo angiogenesis study of KPs treatment., Key Findings: Data showed that rats in the L-NAME group developed severe hypertension, proteinuria, placental damage, and embryo resorption. Pre-administration of KPs significantly reduced hypertension, proteinuria, improved generalized endothelial dysfunction, and decreased levels of anti-HIF-1α, sFLT1, anti-TNF-α, and IL-6 in the placenta of SHRSP rats. In ex vivo CAM study, L-NAME administration in chicken embryos resulted in lower vessel density and hemorrhage; however, angiogenesis was observed after KPs-HD treatment., Significance: The results indicate that kefir peptides improve renal lesions, prevent renal parenchyma damage, and balance endothelial and angiogenic dysfunction in both maternal and fetal sites in L-NAME-induced SHRSP pregnant rats., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chuan-Mu Chen reports financial support was provided by Ministry of Science and Technology in Taiwan. Chuan-Mu Chen reports financial support was provided by Ministry of Education in Taiwan. There are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Endothelial dysfunction exacerbates hypertension and other vascular complications in diabetes mellitus (DM). Circulating microparticles (MPs) and extracellular vesicles released in patients with DM have emerged as novel regulators of endothelial dysfunction. The obstruction of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications. Their impact on the obstruction of MRs on circulating MPs and endothelial dysfunction in DM remains unclear. DM was induced in mice through a single intravenous dose of streptozotocin (STZ; 200 mg/kg). Esaxerenone (ESAX; 3 mg/kg/day), a MR blocker was administered via diet for 8 weeks. In this study, the aortas of the DM group showed the endothelial dysfunction and the administration of ESAX ameliorated the endothelial-dependent responses. Moreover, ESAX influences the impaired endothelial-dependent responses of DM-derived MPs. Interestingly, MP levels increased in DM whereas decreased after ESAX administration. In the aorta, the DM-derived MPs increased the expression of intercellular adhesion molecule-1 (ICAM-1). ESAX inhibited the adhesion of DM-derived MPs. Moreover, the ICAM-1 inhibitor A205804 shows similar effects as ESAX. These results indicate that the release and adhesion properties of MPs can be partially obstructed by ESAX via the ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of ESAX., (© 2024. The Author(s).)

Estrogens have a well-known protective role in the development of the metabolic syndrome. Nevertheless, recent epidemiological data question the cardioprotective effect of estrogens in obese and diabetic women. In this context, white adipose tissue (WAT) becomes dysfunctional, which has an impact on the cardiovascular system. The aim of the study was to elucidate the role of 17β-estradiol (E2) in the interplay between adipose tissue and endothelial function in an animal model of diabesity. We used ZDF (fa/fa) female rats subjected to ovariectomy (OVA), OVA + E2 or sham operated, as well as non-obese non-diabetic ZDF (fa/+) rats. Endothelial function and vascular remodeling markers were assessed in the aorta, while mitochondrial function, oxidative stress, and adiponectin production were analyzed in gonadal WAT. Conditioned media from gonadal WAT explants were used to assess the effects of WAT secretome on HUVEC. Additionally, the adiponectin receptor agonist AdipoRON and E2 were utilized to examine potential interactions. Ovariectomy ameliorated the WAT dysfunction associated to the obese and diabetic state and promoted adiponectin secretion, effects that were linked to a reduction of endothelial dysfunction and inflammatory markers in the aorta of OVA rats and in HUVEC treated with OVA-conditioned media. Our findings provide evidence supporting the idea that in the context of obesity and diabetes, ovariectomy improves WAT secretome and positively impacts endothelial function, suggesting a detrimental role for E2. Additionally, our results point to adiponectin as the primary driver of the effects exerted by ovariectomy on the adipovascular axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vascular endothelial injury is closely related to the progression of various cardio-cerebrovascular diseases. Whether Human Urinary Kallidinogenase (HUK) has a protective effect on endothelial injury remains unclear. This study established an in vivo model of rat common carotid artery intima injury and an in vitro model of human umbilical vein endothelial cell (HUVECs) injury induced by hydrogen peroxide (H 2 O 2 ). To explore the protective effect and mechanism of HUK on endothelial injury. In vivo, HUK can reduce the hyperplasia and lumen stenosis of rat common carotid artery after intimal injury, and promote the fluorescence expression of vWF in the common carotid artery. HUK also activated the Nrf2/HO-1 signaling pathway in rat common carotid artery tissue to reduce endothelial damage. In vitro, HUK can inhibit the H 2 O 2 -induced decline in HUVECs activity, improve the migration ability of HUVECs induced by H 2 O 2 , inhibit the apoptosis and necrosis of HUVECs and the generation of ROS, and regulate the expression of VEGFA, ET-1 and eNOS proteins related to endothelial function in cells. The Nrf2/HO-1 signaling pathway is activated, and the HO-1 specific inhibitor zinc porphyrin (ZnPP) can partially reverse the protective effect of HUK on H 2 O 2 -induced HUVECs injury in terms of cell migration, necrosis and oxidative stress. The Nrf2/HO-1 signaling pathway plays an important role in the regulation of migration, necrosis and oxidative stress of HUVECs cells. HUK has a protective effect on vascular endothelial injury. HUK can inhibit oxidative stress and apoptotic necrosis by activating Nrf2/HO-1 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Postmenopausal cardiovascular health is a critical determinant of longevity. Consumption of beetroot juice (BR) and other nitrate-rich foods is a safe, effective non-pharmaceutical intervention to increase systemic bioavailability of the vasoprotective molecule, nitric oxide, through the exogenous nitrate (NO 3 - )-nitrite (NO 2 - )-nitric oxide (NO) pathway. We hypothesized that a single dose of nitrate-rich beetroot juice (BR nitrate 600 mg NO 3 - /140 mL, BR placebo ∼ 0 mg/140 mL) would improve resting endothelial function and resistance to ischemia-reperfusion (IR) injury to a greater extent in early-postmenopausal (1-6 years following their final menstrual period (FMP), n  = 12) compared to late-postmenopausal (6+ years after FMP, n  = 12) women. Analyses with general linear models revealed a significant ( p  < 0.05) time * treatment interaction effect for brachial artery adjusted flow-mediated dilation (FMD). Pairwise comparisons revealed that adjusted FMD was significantly lower following IR-injury in comparison to all other time points with BR placebo (early FMD 2.51 ± 1.18%, late FMD 1.30 ± 1.10, p  < 0.001) and was lower than post-IR with BR nitrate (early FMD 3.84 ± 1.21%, late FMD 3.21 ± 1.13%, p  = 0.014). A single dose of BR nitrate significantly increased resting macrovascular function in the late postmenopausal group only ( p  = 0.005). Considering the postmenopausal stage-dependent variations in endothelial responsiveness to dietary nitrate, we predict differing mechanisms underpin macrovascular protection against IR injury., Competing Interests: The authors declare there are no competing interests.

Purpose: To uncover the possible effects of zerumbone on the viability, motility, and angiogenesis of human retinal microvascular endothelial cells and to clarify the mechanism., Methods: 5-Ethynyl-2'-deoxyuridine assays were conducted to confirm the effects of zerumbone on the viability of human retinal microvascular endothelial cells. Wound healing, tube formation, and immunoblot assays were conducted to confirm the role of zerumbone in human retinal microvascular endothelial cell motility and angiogenesis, and regulation on vascular endothelial growth factor expression. ELISA was performed to confirm its effects on vascular endothelial growth factor secretion. Colivelin was used to activate the STAT3., Results: We revealed that zerumbone suppressed the viability of human retinal microvascular endothelial cells. Zerumbone restrained the motility and angiogenesis of human retinal microvascular endothelial cells via targeting STAT3 and regulating the expression and secretion of vascular endothelial growth factor in vitro . Zerumbone treatment suppressed the angiogenesis, whereas Colivelin treatment reversed the suppression of angiogenesis caused by zerumbone., Conclusion: Zerumbone restrained the viability, motility and angiogenesis of human retinal microvascular endothelial cells by inhibiting vascular endothelial growth factor expression.

Background and Purpose: Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline-rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes., Experimental Approach: New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings., Key Results: Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC., Conclusion and Implications: Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-N G -Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D 2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D 2 -receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 μM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 μM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D 2 -like receptors., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats., Background: Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo., Methods: Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % → 5 %)., Results: Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol., Conclusions: Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction., Competing Interests: Declaration of competing interest The authors declare that no conflicts of interest exist and have no financial interests associated with the present study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Endothelial dysfunction, which is marked by a reduction in nitric oxide (NO) production or an imbalance in relaxing and contracting factor levels, exacerbates atherosclerosis by promoting the production of cell adhesion molecules and cytokines. This study aimed to investigate the effects of Limosilactobacillus reuteri HY7503, a novel probiotic isolated from raw milk, on endothelial dysfunction. Five lactic acid bacterial strains were screened for their antioxidant, anti-inflammatory, and endothelium-protective properties; L. reuteri HY7503 had the most potent effect. In a mouse model of angiotensin II-induced endothelial dysfunction, L. reuteri HY7503 reduced vascular thickening (19.78%), increased serum NO levels (226.70%), upregulated endothelial NO synthase ( eNOS ) expression in the aortic tissue, and decreased levels of cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) and serum cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]). In TNF-α-treated human umbilical vein endothelial cells (HUVECs), L. reuteri HY7503 enhanced NO production and reduced cell adhesion molecule levels. In HUVECs, surface-layer proteins (SLPs) were more effective than extracellular vesicles (exosomes) in increasing NO production and decreasing cell adhesion molecule levels. These findings suggested that L. reuteri HY7503 may serve as a functional probiotic that alleviates endothelial dysfunction.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and is associated with increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and reductions in nitric oxide (NO) levels. Placental ischemia and hypoxia are hypothesized as initial pathophysiological events of PE. Nitrite (NO metabolite) may be recycled back to NO in ischemic and hypoxic tissues. Therefore, this study examined the sodium nitrite effects in an experimental model of PE. Pregnant rats received saline (Preg group) or sodium nitrite (Preg + Na-Nitrite group). Pregnant rats submitted to the placental ischemia received saline (RUPP group) or sodium nitrite (RUPP + Na-Nitrite group). Blood pressure, placental and fetal weights, and the number of pups were recorded. Plasma levels of NO metabolites and sFlt-1 were also determined. Vascular and endothelial functions were also measured. Blood pressure, placental and fetal weights, the number of pups, NO metabolites, sFlt-1 levels, vascular contraction, and endothelium-dependent vasodilation in the RUPP + Na-Nitrite rats were brought to levels comparable to those in Preg rats. In conclusion, sodium nitrite may counteract the reductions in NO and increases in sFlt-1 levels induced by the placental ischemia model of PE, thus suggesting that increased blood pressure and vascular and endothelial dysfunctions may be attenuated by sodium nitrite-derived NO.

Endothelial dysfunction (ED) is closely associated with most cardiovascular diseases. Experimental models are needed to analyze the potential impact of ED on cardioprotection in constant pressure Langendorff systems (CPLS). One cardioprotective strategy against ischemia/reperfusion injury (I/RI) is conditioning with the lipid emulsion Intralipid (IL). Whether ED modulates the cardioprotective effect of IL remains unknown. The aim of the study was to transfer a protocol using a constant flow Langendorff system for the induction of ED into a CPLS, without the loss of smooth muscle cell functionality, and to analyze the cardioprotective effect of IL against I/RI under ED. In isolated hearts of male Wistar rats, ED was induced by 10 min perfusion of a Krebs-Henseleit buffer containing 60 mM KCl (K+), and the vasodilatory response to the vasodilators histamine (endothelial-dependent) and sodium-nitroprusside (SNP, endothelial-independent) was measured. A CPLS was employed to determine cardioprotection of pre- or postconditioning with 1% IL against I/RI. The constant flow perfusion of K+ reduced endothelial response to histamine but not to SNP, indicating reduced vasodilatory functionality of endothelial cells but not smooth muscle cells. Preconditioning with IL reduced infarct size and improved cardiac function while postconditioning with IL had no effect. The induction of ED neither influenced infarct size nor affected the cardioprotective effect by preconditioning with IL. This protocol allows for studies of cardioprotective strategies under ED in CLPS. The protection by preconditioning with IL seems to be mediated independently of a functional endothelium.

Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the vascular system, particularly targeting ECs for therapeutic purposes. However, the complex interactions between vascular ECs and nanocarriers present significant challenges for the development and clinical translation of nanotherapeutics. This review assesses recent advancements and key strategies in employing nanocarriers for drug delivery to vascular ECs. It suggested that through precise physicochemical design and surface modifications, nanocarriers can enhance targeting specificity and improve drug internalization efficiency in ECs. Additionally, we elaborated on the applications of nanocarriers specifically designed for targeting ECs in the treatment of cardiovascular diseases, cancer metastasis, and inflammatory disorders. Despite these advancements, safety concerns, the complexity of in vivo processes, and the challenge of achieving subcellular drug delivery remain significant obstacles to the effective targeting of ECs with nanocarriers. A comprehensive understanding of endothelial cell biology and its interaction with nanocarriers is crucial for realizing the full potential of targeted drug delivery systems., (© 2024. The Author(s).)

Introduction: Endothelial dysfunction is an early precursor of atherosclerosis and is common in patients with psoriasis, presumably primarily due to psoriasis-related inflammation. We investigated endothelial function, arterial stiffness, and circulating markers of endothelial activation in young patients with psoriasis vulgaris of varying severity, all of whom were effectively treated achieving PASI 90., Methods: We conducted a cross-sectional study of 80 patients (54 men/26 women, 30-45 years) who were effectively treated with topical therapy, methotrexate, adalimumab, secukinumab or guselkumab, and 20 healthy controls. Endothelial dysfunction was measured by flow-mediated dilation and arterial stiffness was measured by pulse wave velocity and common carotid artery stiffness. The following circulating biomarkers of endothelial activation were measured: ICAM-1, VCAM-1, E- and P-selectin, GDF-15, and TRAIL., Results: Endothelial function and arterial stiffness parameters did not differ between patients with effectively treated psoriasis and the control group. Circulating endothelial activation biomarkers did not show relevant differences between the groups of effectively treated patients or controls., Discussion: Although cardiovascular disease is the leading cause of morbidity and mortality in patients with psoriasis, effective antipsoriatic treatment appears to slow the progression of atherosclerosis, even when there are cardiovascular risk factors, such as smoking or obesity. This may suggest that antipsoriatic treatment exerts a cardioprotective effect., Conclusions: Our results suggest that early and effective treatment of varying-severity psoriasis vulgaris in young patients appears to prevent arterial dysfunction related to psoriasis and consequent cardiovascular risk.The study is registered at http://clinicaltrials.gov (identifier: NCT05957120)., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Coronary vasomotor dysfunction, an important underlying cause of angina and nonobstructive coronary arteries (ANOCA), encompassing coronary vasospasm, coronary endothelial dysfunction, and/or coronary microvascular dysfunction, is clinically assessed by invasive coronary function testing (ICFT). As ICFT imposes a high burden on patients and carries risks, developing noninvasive alternatives is important. We evaluated whether coronary vasomotor dysfunction is a component of systemic microvascular endothelial and smooth muscle dysfunction and can be detected using laser speckle contrast analysis (LASCA). Forty-three consecutive patients with ANOCA underwent ICFT, with intracoronary acetylcholine, adenosine, and flow measurements, to assess coronary vasomotor dysfunction. Cutaneous microvascular function was assessed using LASCA in the forearm, combined with vasodilators acetylcholine, sodium nitroprusside, and insulin and using EndoPAT, by measuring the reactive hyperemia index (RHI). Of the 43 included patients with ANOCA (79% women, 59 ± 9 yr old), 38 patients had coronary vasomotor dysfunction, including 28 with coronary vasospasm, 26 with coronary endothelial dysfunction, and 18 with coronary microvascular dysfunction, with overlapping endotypes. Patients with and without coronary vasomotor dysfunction had similar peripheral flow responses to acetylcholine, insulin, and RHI. In contrast, coronary vasomotor dysfunction was associated with lower peripheral flow responses to sodium nitroprusside ( P < 0.001). An absolute flow response to sodium nitroprusside of 83.95 APU resulted in 86.1% sensitivity and 80.0% specificity for coronary vasomotor dysfunction (area under the ROC curve, 0.883; P = 0.006). In conclusion, this study provides evidence of systemic vascular smooth muscle dysfunction in patients with ANOCA with coronary vasomotor dysfunction and the diagnostic value of peripheral microvascular function testing as a noninvasive tool for detecting coronary vasomotor dysfunction. NEW & NOTEWORTHY This study provides proof of concept that assessment of the peripheral vasculature, particularly vascular smooth muscle cells measured using the LASCA technology holds potential as a noninvasive tool for detecting coronary vasomotor dysfunction. This finding highlights the potential of the LASCA technology in, for example, medication studies for coronary vasomotor dysfunction, especially when investigating whether medication improves vascular function, as repeated peripheral measurements are less invasive than invasive coronary function testing, the current gold standard.

Exposure to VEGF-A 165 a over several days leads to a persistent dysfunction of the very tight barrier formed by immortalized endothelial cells of the bovine retina (iBREC). Elevated permeability of the barrier is indicated by low cell index values determined by electric cell-substrate impedance measurements, by lower amounts of claudin-1, and by disruption of the homogenous and continuous staining of vascular endothelial cadherin at the plasma membrane. Because of findings that suggest modulation of VEGF-A's detrimental effects on the inner blood-retina barrier by the angiogenic growth factor angiopoietin-2, we investigated in more detail in vitro whether this growth factor indeed changes the stability of the barrier formed by retinal endothelial cells or modulates effects of VEGF-A. In view of the clinical relevance of anti-VEGF therapy, we also studied whether blocking VEGF-A-driven signaling is sufficient to prevent barrier dysfunction induced by a combination of both growth factors. Although angiopoietin-2 stimulated proliferation of iBREC, the formed barrier was not weakened at a concentration of 3 nM: Cell index values remained high and expression or subcellular localization of claudin-1 and vascular endothelial cadherin, respectively, were not affected. Angiopoietin-2 enhanced the changes induced by VEGF-A 165 a and this was more pronounced at lower concentrations of VEGF-A 165 a. Specific inhibition of the VEGF receptors with tivozanib as well as interfering with binding of VEGF-A to its receptors with bevacizumab prevented the detrimental effects of the growth factors; dual binding of angiopoietin-2 and VEGF-A by faricimab was marginally more efficient. Uptake of extracellular angiopoietin-2 by iBREC can be efficiently prevented by addition of faricimab which is also internalized by the cells. Exposure of the cells to faricimab over several days stabilized their barrier, confirming that inhibition of VEGF-A signaling is not harmful to this cell type. Taken together, our results confirm the dominant role of VEGF-A 165 a in processes resulting in increased permeability of retinal endothelial cells in which angiopoietin-2 might play a minor modulating role., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Excess sodium consumption contributes to arterial dysfunction in humans. The C57BL/6 strain of mice has been used to identify mechanisms by which arterial dysfunction occurs after excess sodium consumption. However, there are concerns that C57BL/6 mice have strain-specific resistance to high-sodium (HS) diet-induced hypertension. To address this concern, we performed a meta-analysis to determine if excess sodium consumption in C57BL/6 mice induces arterial dysfunction. Databases were searched for HS versus standard diet studies that measured arterial function [i.e., systolic blood pressure (BP), endothelium-dependent dilation (EDD), and central arterial stiffness] in C57BL/6 mice. A total of 39 studies were included, demonstrating that the HS condition resulted in higher systolic BP than control mice with a mean difference of 9.8 mmHg (95% confidence interval [CI] = [5.6, 14], P < 0.001). Subgroup analysis indicated that the systolic BP was higher in HS compared with the control condition when measured during night compared with daytime with telemetry ( P < 0.001). We also identified that the difference in systolic BP between HS and control was ∼2.5-fold higher when administered through drinking water than through food ( P < 0.001). A total of 12 studies were included, demonstrating that the HS condition resulted in lower EDD than control with a weighted mean difference of -12.0% (95% CI = [-20.0, -4.1], P = 0.003). It should be noted that there was considerable variability across studies with more than half of the studies showing no effect of the HS condition on systolic BP or EDD. In summary, excess sodium consumption elevates systolic BP and impairs EDD in C57BL/6 mice. NEW & NOTEWORTHY C57BL/6 mice are perceived as resistant to high-sodium diet-induced arterial dysfunction. This meta-analysis demonstrates that excess sodium consumption elevates blood pressure and impairs endothelium-dependent dilation in C57BL/6 mice. Nighttime measurements show more pronounced blood pressure elevation. In addition, sodium administration via drinking water, compared with food, induces a greater blood pressure elevation. These findings may be influenced by outlier studies, as the majority of studies showed no adverse effect of excess sodium consumption on arterial function.

Historical exclusion of females in research has been, in part, due to the perceived influence of natural menstrual (NAT) and oral contraceptive pill (OCP) cycles on vascular outcomes. NAT and OCP cycle phases may influence brachial artery (BA) endothelial function, however, findings are mixed. Minimal research has examined arterial stiffness, smooth muscle, and lower limb endothelial function. The purpose of this study was to investigate the influence of NAT and OCP cycles on cardiovascular outcomes and cellular regulation. Forty-nine premenopausal females ( n = 17 NAT, n = 17 second generation OCP, n = 15 third generation OCP) participated in two randomized order visits in the low (LH, early follicular/placebo) and high (HH, midluteal/active) hormone cycle phases. BA and superficial femoral artery (SFA) endothelial function [flow-mediated dilation (FMD) test], smooth muscle function (nitroglycerine-mediated dilation test), and carotid and peripheral (pulse wave velocity) arterial stiffness were assessed. Cultured female human endothelial cells were exposed to participant serum for 24 h to examine endothelial nitric oxide synthase (eNOS) and estrogen receptor-α (ERα) protein content. BA FMD was elevated in the HH vs. LH phase, regardless of group (HH, 7.7 ± 3.5%; LH, 7.0 ± 3.3%; P = 0.02); however, allometric scaling for baseline diameter resulted in no phase effect (HH, 7.6 ± 2.6%; LH, 7.1 ± 2.6%; P = 0.052, d = 0.35). SFA FMD, BA, and SFA smooth muscle function, arterial stiffness, and eNOS and ERα protein content were unaffected. NAT and OCP phases examined have minimal influence on vascular outcomes and ERα-eNOS pathway, apart from a small effect on BA endothelial function partially explained by differences in baseline artery diameter. NEW & NOTEWORTHY Comprehensive evaluation of the cardiovascular system in naturally cycling and second and third generation OCP users indicates no major influence of hormonal phases examined on endothelial function and smooth muscle function in the arteries of the upper and lower limbs, arterial stiffness, or underlying cellular mechanisms. Study findings challenge the historical exclusion of female participants due to potentially confounding hormonal cycles; researchers are encouraged to consider the hormonal environment in future study design.

Objective: This paper was aimed at unveiling the effect of low-molecular-weight heparin calcium (LMWH) combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function, and pregnancy outcome in early-onset severe preeclampsia (EOSP)., Methods: Pregnant women with EOSP were divided into the control group and the study group, each with 62 cases. Patients in the control group were treated with labetalol and magnesium sulfate, and those in the study group were treated with LMWH in combination with the control grou Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), 24-h urine protein, coagulation indices [D-dimer (D-D), plasma fibrinogen (Fg), prothrombin time (PT), activated partial thromboplastin time (APTT), and prothrombin time (TT)], endothelial function [endothelin (ET-1) and nitric oxide (NO)], oxidative stress indices [oxidized low-density lipoproteins (ox-LDL), lipid peroxidation (LPO), superoxide dismutase (SOD), and malondialdehyde (MDA)], pregnancy outcome, and adverse effects occurred in the two groups were compared., Results: After treatment, lower SBP, DBP, and 24-h urine protein levels; lower Fg and D-D levels; higher PT, APPT, and TT levels; higher NO levels; lower ET-1 levels; lower ox-LDL, MDA, and LPO levels; higher SOD levels; and lower incidence of adverse pregnancy and adverse reactions were noted in the study group in contrast to the control group., Conclusion: EOSP patients given with LMWH combined with magnesium sulfate and labetalol can effectively reduce the patient's blood pressure and urinary protein level; improve coagulation function, oxidative stress, and vascular endothelial function indices; reduce the adverse pregnancy outcomes; and improve the safety of treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Numerous interventional studies have revealed the beneficial impact of curcumin supplementation on inflammation, oxidative stress, and endothelial function biomarkers, but the findings are still inconsistent. Thus, this study was conducted to investigate the effects of curcumin supplementation on inflammation, oxidative stress, and endothelial function biomarkers. A meta-analyses of randomized clinical trials was performed by searching PubMed, Embase, Scopus, and Web of Science up to March 31, 2024. Pooled estimates of 21 meta-analyses revealed that curcumin significantly reduced CRP (weighted mean difference (WMD) = -0.87; 95 % CI: - 1.14, - 0.59, P< 0.001), tumor-necrosis factor-alpha (TNF-α) (WMD = -2.72; 95 % CI: -4.05, -1.38; P< 0.001), interleukin-6 (IL-6) (WMD = -0.97, 95 % CI: -1.40, -0.54; P< 0.001), malondialdehyde (MDA) (Effect size (ES) = -0.81; 95 % CI: -1.39, -0.23, P = 0.006) and pulse wave velocity (PWV) (WMD = -45.60; 95 % CI: -88.16, -3.04, P = 0.036), and increased flow-mediated dilation (FMD) (WMD = 1.64, 95 % CI: 1.06, 2.22, P < 0.001), catalase (CAT) (WMD = 10.26; 95 % CI: 0.92, 19.61, P= 0.03), glutathione peroxidase (GPx) (WMD = 8.90; 95 % CI: 6.62, 11.19, P <0.001), and superoxide dismutase (SOD) levels (WMD = 20.51; 95 % CI: 7.35, 33.67, P= 0.002 and SMD = 0.82; 95 % CI: 0.27, 1.38, P= 0.004). However, curcumin did not significantly change total antioxidant capacity (TAC) (ES = 0.29; 95 % CI: -0.09, 0.66, P= 0.059). These results suggest that curcumin has a beneficial effect on CRP, IL-6, TNF-α, SOD, GPx, CAT, MDA, PWV, and FMD levels and may be an effective adjunctive therapy for improving inflammation, oxidative stress, and endothelial function. Registration number: PROSPERO, CRD42024539018., Competing Interests: Declaration of Competing Interest No conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication., (© 2024. The Society for In Vitro Biology.)

The current study explored melatonin (MEL) and its receptors, including MEL type 1 receptor (MT1) receptor and MEL type 2 receptor (MT2), along with the angiotensin-converting enzyme 2 (ACE 2 ), influence on vascular responses to angiotensin II (Ang II) in rat aortic segments of normal and diabetic rats. The isolated aortic segments were exposed to MEL, the MEL agonist; ramelteon (RAM), the MEL antagonist; luzindole (LUZ), and an ACE 2 inhibitor (S, S)-2-(1-Carboxy-2-(3-(3,5-dichlorobenzyl)-3 H-imidazol-4-yl)-ethylamino)-4-methylpentanoic acid,) on Ang II-induced contractions in non-diabetic normal endothelium (non-DM E+), non-diabetic removed endothelium (non-DM E-), and streptozotocin-induced diabetic endothelium-intact (STZ-induced DM E+) rat aortic segments, as well as their combination in STZ-induced DM E + segments, were also included. The current results showed that MEL and RAM shifted Ang II dose-response curve (DRC) to the right side in non-DM E + and non-DM E- aorta but not in STZ-induced DM E + aorta. However, ACE 2 inhibition abolished Ang II degradation only in STZ-induced DM E + segments, not in non-DM E + segments. Additionally, the combinations of MEL-LUZ and RAM-ACE 2 inhibitor caused a rightward shift in Ang II response in STZ-induced DM E + segments, while the MEL-LUZ combination decreased Ang II DRC. The findings suggest that the effects of MEL and ACE 2 inhibitor on Ang II responses depend on the condition of the endothelium and the distribution of the MEL receptors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10 -10 -10 -1 M) and insulin (10 -8 -10 -4 M) in control sites and sites treated with 15 mM l-NAME [ N G -nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine ( P = 0.006) and insulin ( P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC ( P = 0.009) but had no effect in GDM ( P = 0.306). Ascorbate treatment increased acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC ( P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance. NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Phylloquinon (PK) and menaquinones (MK) are both naturally occurring compounds belonging to vitamin K group. Present study aimed to comprehensively analyze the influence of PK in several models of vascular dysfunction to determine whether PK has vasoprotective properties, similar to those previously described for MK. Effects of PK and MK on endothelial dysfunction were studied in ApoE/LDLR -/- mice in vivo, in the isolated aorta incubated with TNF, and in vascular cells as regard inflammation and cell senescence (including replicative and stress-induced models of senescence). Moreover, the vascular conversion of exogenous vitamins to endogenous MK-4 was analyzed. PK, as well as MK, given for 8 weeks in diet (10 mg/kg) resulted in comparable improvement in endothelial function in the ApoE/LDLR -/- mice. Similarly, PK and MK prevented TNF-induced impairment of endothelium-dependent vasorelaxation in the isolated aorta. In in vitro studies in endothelial and vascular smooth muscle cells, we identified that both PK and MK displayed anti-senescence effects via decreasing DNA damage while in endothelial cells anti-inflammatory activity was ascribed to the modulation of NFκB activation. The activity of PK and MK was comparable in terms of their effect on senescence and inflammation. Presence of endogenous synthesis of MK-4 from PK in aorta and endothelial and smooth muscle cells suggests a possible involvement of MK in vascular effects of PK. In conclusion, PK and MK display comparable vasoprotective effects, which may be ascribed, at least in part, to the inhibition of cell senescence and inflammation. The vasoprotective effect of PK in the vessel wall can be related to the direct effects of PK, as well as to the action of MK formed from PK in the vascular wall., (© 2024. The Author(s).)

Background: Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction., Purpose: Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms., Methods: A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions., Results: PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction., Conclusion: PA activates AMPK and ameliorates endothelial dysfunction during hypertension., Competing Interests: Declaration of competing interest All the authors have declared that no conflicts of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl (breakpoint cluster region-Abelson proto-oncogene) KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs., Competing Interests: I.Z. Jaffe is a consultant at Boeringer Ingelheim. The other authors report no conflicts.

Aim: This study aimed to investigate the acute effects of dietary nitrate ingestion through l-arginine supplementation or dehydrated beet consumption on endothelial function in chronic obstructive pulmonary disease (COPD) patients. The secondary outcome was to analyze arterial stiffness, plasma nitrate, and nitrate/protein concentration., Methods: In this randomized crossover study, subjects with COPD underwent three series of supplementation: (1) l-arginine, (2) dehydrated beetroot, and (3) a placebo that appeared like the other supplements. Each intervention lasted 14 days, with a 7-day washout period between series. Participants underwent endothelial function assessment using flow-mediated dilatation (FMD), and plasma nitrate levels were measured at the end of each supplementation series., Results: Seventeen subjects (twelve male) completed the study protocol. Only five subjects presented endothelial dysfunction (RHI ≤0.51) at baseline. The mean baseline characteristics included age 66.5 ± 9.4 years, BMI 27.5 ± 4.5 kg/m 2 , FEV 1, 0.79 (0.67-1.06) L. There were no differences (p > 0.05) between the groups or from pre-to post-interventions for RHI and arterial stiffness index (AIx) values, as well as parameters of endothelium-dependent vasodilation, such as blood flow velocity (BFV), shear stress, shear rate, FMD (mm), and FMD%. There was also no differences (p > 0.05) between the groups or from pre-to post-interventions plasma nitrate levels., Conclusions: Acute dietary supplementation with nitrates, at the doses provided, did not show a significant improvement in endothelial function assessed by FMD, EndoPAT, or plasma nitrate levels in COPD. These findings suggest that a higher dose or prolonged supplementation might be required to achieve a therapeutic effect., Competing Interests: Declaration of competing interest On Behalf of the authors, I declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We developed a covalent antithrombin-heparin complex (ATH) with superior In vivo anticoagulant efficacy compared to non-covalent antithrombin (AT) + unfractionated heparin (H). Previous in vitro studies of ATH, investigating the mechanisms behind its efficacy, were done in the absence of endothelium. Since the endothelial surface modulates hemostasis, we investigated its impact on the in vitro anticoagulant properties of ATH and AT+H. Discontinuous second order rate constant enzyme inhibition assays, fibrin formation, and plasma clot generation were performed in the presence of ATH or AT+H, with and without endothelium present. ATH had an increased rate of direct inhibition of IIa and Xa, and increased inhibition of IIa-induced fibrin formation, compared to AT+H. When compared at equal anti-Xa levels, ATH was less effective than AT+H at catalyzing inhibition of plasma clot generation. These results were found in both the presence and absence of endothelium. Endothelium decreased the rate of IIa inhibition, and reduced clot time in IIa-induced fibrin formation and plasma clot generation assays, for both ATH and AT+H. Endothelium did not impact the activity of ATH differently to AT+H. This supports the growing body of evidence suggesting ATH may be a beneficial anticoagulant for potential clinical use., (© 2024. The Author(s).)

Endothelial dysfunction occurs prior to atherosclerosis, which is an independent predictor of cardiovascular diseases (CVDs). Diabetes mellitus impairs endothelial function by triggering oxidative stress and inflammation in vascular tissues. Isoliquiritigenin (ISL), one of the major bioactive ingredients extracted from licorice, has been reported to inhibit inflammation and oxidative stress. However, the therapeutic effects of ISL on ameliorating type 2 diabetes (T2D)-associated endothelial dysfunction remain unknown. In our animal study, db / db male mice were utilized as a model for T2D-associated endothelial dysfunction, while their counterpart, heterozygote db / m + male mice, served as the control. Mouse brain microvascular endothelial cells (mBMECs) were used for in vitro experiments. Interleukin-1β (IL-1β) was used to induce endothelial cell dysfunction. ISL significantly reversed the impairment of endothelium-dependent relaxations (EDRs) in db / db mouse aortas. ISL treatment decreased ROS (reactive oxygen species) levels in db / db mice aortic sections and IL-1β-treated endothelial cells. Encouragingly, ISL attenuated the overexpression of pro-inflammatory factors MCP-1, TNF-α, and IL-6 in db / db mouse aortas and IL-1β-impaired endothelial cells. The NOX2 (NADPH oxidase 2) overexpression was inhibited by ISL treatment. Notably, ISL treatment restored the expression levels of IL-10, SOD1, Nrf2, and HO-1 in db / db mouse aortas and IL-1β-impaired endothelial cells. This study illustrates, for the first time, that ISL attenuates endothelial dysfunction in T2D mice, offering new insights into the pharmacological effects of ISL. Our findings demonstrate the potential of ISL as a promising therapeutic agent for the treatment of vascular diseases, paving the way for the further exploration of novel vascular therapies.

Objective: This article focus on patients with moderate-to-severe periodontitis and periodontitis patients with cardiovascular disease. After they received periodontal initial therapy or antimicrobial drug treatment, was there any improvement in endothelial function during short- and long-term followups?, Method: Relevant randomized controlled trials and clinical trials up to 30th June 2024 were identified and retrieved from electronic databases including PubMed, Cochrane Library, Web of Science and CNKI databases, with periodontitis therapy, periodontal disease and endothelial function as the keywords. The weighted (WMD) or standardized mean difference (SMD) was calculated using a fixed- or random-effect model and assessed heterogeneous results., Result: Generally, 14 studies published between 2004 and 2022 were eligible for the meta-analysis, which are all randomised clinical trials. A total of 491 periodontitis patients were screened. All participants received whole-mouth supragingival and subgingival scaling and root planing of the teeth, some trials combined with antimicrobial drug treatment as well as extracting teeth that could not be saved. The outcome indicators were measured by flow-mediated dilatation(FMD) levels. The results of the short term (≤3 months) periodontitis initial therapy group showed positive results (WMD = -3.78,95%CI = [-5.49,-2.07], P<0.0001), while the results of the long term (6 months) periodontitis therapy group exhibited significant difference (WMD = -0.96,95%CI = [-2.06,0.14],P = 0.09). Furthermore, study population were categorized according to the severity of periodontitis, the presence of comorbidities, endothelial dysfunction, and the inclusion of extractions and antimicrobial therapy in the treatment process. The effects of each of these factors on FMD were explored and the results of these subgroups all support periodontitis therapy., Conclusion: The results showed that periodontal treatment enhances endothelial function. Additionally, after subgroup analysis of long-term and short-term follow-up, patients with severe periodontitis, and different periodontal treatments, periodontal therapy was shown to increase FMD levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lyu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Breast cancer is among the highest causes of morbidity and mortality in women. Trastuzumab therapy, which is known to be significantly cardiotoxic, is mainly used to treat patients with resistant breast cancer, including estrogen receptor-positive type. We aimed to show the effects of trastuzumab therapy on endothelial functions of breast cancer patients., Methods: In this study, a total of 26 participants (24 female and 2 male patients, minimum age: 38 years, maximum age: 79 years, and mean age 57.3±12.7 years) were enrolled in the study. For the statistical evaluation of data, we classified the participants of the study as follows: Pretreatment: Before trastuzumab therapy; Treatment Period 1: 1 month after the first dose of trastuzumab; Treatment Period 2: 4 months after the first dose of trastuzumab; Treatment Period 3: 12 months after the first dose of trastuzumab. We conducted repeated-measures analysis of variance (Greenhouse-Geisser) and paired-sample t-tests to statistically compare the groups using flow-mediated dilation measurements., Results: We determined that there are statistically significant differences between flow-mediated hyperemia and ratio values (flow-mediated dilation) of the groups (p<0.009 and p<0.001, respectively)., Conclusion: Our data indicate that trastuzumab therapy could have negative effects on endothelial functions in breast cancer patients.

Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr&#95;Spermidine and MpJ&#95;Spermidine) for 8 weeks or as control (lpr&#95;Control and MpJ&#95;Control). lpr&#95;Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr&#95;Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.

Nailfold capillaroscopy is a non-invasive investigation, which allows for the study of the microvasculature (anatomical and functional). Rheumatoid arthritis (RA) is associated with a high risk of cardiovascular atherosclerotic diseases, with endothelial dysfunction (macrovascular and microvascular) representing the first step in atherosclerosis development. The aim of this study is represented by the assessment of microvascular endothelial dysfunction in RA patients by means of nailfold capillaroscopy and to assess its evolution after a period of 12 months of anti TNF-alpha treatment. The study included 70 consecutive patients with RA and 70 healthy subjects, matched for age and gender, as the control group. Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were evaluated in all patients, but in controls, only rheumatoid factor, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were measured. The RA activity was measured by DAS28. Nailfold capillaroscopy was carried out in all patients and controls, determining the baseline nailfold capillary density (Db), nailfold capillary density during reactive hyperemia (Dh), and nailfold capillary density after venous congestion (Dc). Data were presented as mean ± standard deviation. Statistical analysis was performed using ANOVA and Pearson's correlation, with p < 0.05 being statistically significant. Db, Dh, and Dc were lower in RA patients than in controls ( p < 0.0001), correlating with RA activity and TNF-α ( p < 0.05). After 12 months of anti TNF-α treatment, microvascular endothelial dysfunction improved ( p < 0.0001). Microvascular endothelial dysfunction can be assessed by nailfold capillaroscopy, with anti TNF-α medication contributing to its improvement.

Introduction: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF., Methods and Analysis: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation., Ethics and Dissemination: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal., Prospero Registration Number: CRD42024538148., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare the endothelial coverage of different stents in porcine carotid arteries. Research problem: How effective are polyurethane stents (PU) and PU + rapamycin (PU + RAPA) compared to bare-metal stents on endothelial coverage by neointima in pigs after 28 days?, Methods: The methodology had two phases for an interventional, experimental, prospective study, with three Moura pigs, 12 weeks old and weighing between 19 and 22.5 kg. In phase I, eight stents were implanted in carotid arteries; three stents coated with PU, three coated with PU + RAPA, and two without coating. After 28 days, phase II was carried out, consisting of euthanasia, removal of the stents, to evaluate the exposed area of the stent struts, and the percentage of endothelialization through optical microscopy and scanning electron microscopy., Results: The eight stents implanted with ultrasound sizing and post-dilation with a larger diameter balloon were analyzed by Doppler ultrasound, intravascular ultrasound, and angiography after 28 days., Conclusions: This study showed complete endothelial coverage by the endoluminal neointima of the stent struts, good integration and coverage with the arterial wall, with no exposed struts showing the presence of intimal hyperplasia (whitish tissue).

Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some breakthroughs in recent decades, PH remains incurable. Therefore, innovative clinical treatment methods and drugs for PH are still urgently needed. DYZY01 is a new drug whose main ingredient is high-purity cannabidiol, a non-psychoactive constituent of cannabinoids that was demonstrated to have anti-inflammatory and anti-pyroptosis properties. Several recent studies have found cannabidiol could improve experimental PH, whereas the mechanistic effect of it warrants further investigation. Thus, this study aimed to investigate whether DYZY01 can treat PH by inhibiting inflammation and pyroptosis and to reveal its underlying mechanism. We established hypoxia and monocrotaline (MCT)-induced PH rat models in vivo and treated them with either DYZY01 (10,50 mg/kg/d) or Riociguat (10 mg/kg/d) by oral administration. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and extent of vascular remodeling were measured. Meanwhile, the effect of DYZY01 on human pulmonary arterial endothelial cells (HPAECs) was assessed in vitro. The results indicated that DYZY01 significantly reduced mPAP and RVHI in PH rats and reversed the extent of pulmonary vascular remodeling. This improvement may have been achieved by reducing endothelial cell pyroptosis via inhibiting the NF-κB/NLRP3/Caspase-1 pathway. Furthermore, DYZY01 could improve endothelial vascular function, possibly by regulating the secretion of vasodilator factors and inhibiting the proliferation and migration of pulmonary endothelial cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose-induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT-endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2-related factor 2/heme oxygenase-1/vascular endothelial growth factor/stromal cell-derived factor-1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor-α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet-induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell-specific Ccl7 -knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.

Importance: Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality., Objective: To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL., Design, Setting, and Participants: This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included., Interventions: Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours., Main Outcomes and Measures: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days., Results: Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed., Conclusions and Relevance: In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04123444.

Acute cerebral infarction poses a significant health risk and effective treatment is crucial. This randomized controlled trial assessed the impact of combining Butylphthalide and Atorvastatin on neurological function, quality of life and vascular endothelial function in 124 individuals with acute cerebral infarction. Participants were randomized into control and experimental groups, with the latter receiving the combination therapy. Objective assessments using NIHSS, SS-QOL, MBI and MoCA scales, along with biochemical markers, demonstrated improved outcomes in the experimental group. This study provides evidence for the clinical benefits of the drug combination in managing acute cerebral infarction.

Xuefu zhuyu Tang (XFZYT) is a classic formula used for promoting blood circulation and resolving blood stasis in Traditional Chinese Medicine. Clinical data have indicated that XFZYT plays a significant therapeutic role in diabetes-induced erectile dysfunction (DIED) disease, but the underlying mechanism remains elusive. Male Sprague-Dawley (SD) rats were randomly categorized into normal, model, and treatment groups. The diabetic rat model was established via intraperitoneal injection of streptozotocin. DIED rats were screened using apomorphine, and the number of erections was measured after 8 weeks of XFZYT treatment. Serum nitric oxide (NO) and endothelin-1 levels as well as penile tissue structure alterations were assessed by hematoxylin-eosin staining and electron microscopy. CaSR/PLC/PKC and MEK/ERK/RSK pathway-related proteins in the penile tissue were detected by western blotting (WB) analysis and polymerase chain reaction (PCR). Compared with the blank group, the model group rats showed a significant decrease in weight and erectile function. The pathological damage in the penile tissues of the model rats was indicated by a significantly decreased serum NO level and an increased endothelin-1 content. After treatment with XFZYT, the protein expression of CaSR, PLCβ1, PKCβ, MEK1, ERK1, and RSK1 in the penile tissue was significantly increased. Overall, the treatment group showed significant improvements in the evaluated indexes. In conclusion, this study revealed that XFZYT improves erectile function in diabetic rats, and the underlying mechanism might be linked with the regulation of CaSR/PLC/PKC and related molecules of the MEK/ERK/RSK pathway, which promotes the vascular endothelial diastolic effect., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Prior work has yet to determine whether the reduction of dietary nitrate (NO 3 - ) to NO, via the enterosalivary pathway, may modify cutaneous vascular conductance (CVC) responses to local heating in older women. Changes occurring with the transition to menopause related to hormonal flux, increased adiposity, and/or decreased physical activity may further compound the negative influence of aging on nitric oxide (NO)-dependent CVC. Herein, we characterized changes in NO-dependent CVC following acute ingestion of 140 mL of NO 3 - -rich beetroot juice in 24 older women (age: 65 ± 5 y, BMI: 31.2 ± 3.7 kg/m 2 ). Red blood cell (RBC) flux was measured continuously via laser-Doppler flowmetry on the dorsal aspect of the forearm during local skin heating to 39 °C/44 °C before and 3 h after NO 3 - ingestion. NO-dependent changes in CVC were calculated as RBC flux/mean arterial blood pressure at 39 °C and normalized as a proportion of maximal CVC at 44 °C (%CVCmax). Changes (Δ) in fractional exhaled NO (FeNO) following NO 3 - ingestion were used an index of NO bioavailability. Despite increased FeNO (+81 ± 70 %, P < 0.001), %CVCmax at 39 °C was reduced (-16 ± 10 %, P < 0.001) following NO 3 - ingestion. A greater reduction in %CVCmax was weakly to moderately associated with higher body fat% (r = 0.45 [0.05-0.72], P = 0.029), central adiposity% (r = 0.50 [0.13-0.75], P = 0.012), neutrophil% (r = 0.42 [0.02-0.70], P = 0.041), and higher neutrophil to lymphocyte ratio (r = 0.49 [0.11-0.75], P = 0.016). These findings demonstrate a single dose of dietary NO 3 - does not promote CVC responses to local heating in sedentary older women with overweight and obesity. Correlation with multiple biomarkers suggest systemic inflammation may be involved., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The long-term consequences of electronic cigarette (Ecig) use in humans are not yet known, but it is known that Ecig aerosols contain many toxic compounds of concern. We have recently shown that Ecig exposure impairs middle cerebral artery (MCA) endothelial function and that it takes 3 days for MCA reactivity to return to normal. However, the sources contributing to impairment of the endothelium were not investigated. We hypothesized that the increased levels of oxidative stress markers in the blood are correlated with impaired MCA reactivity. We used electron paramagnetic resonance (EPR) spectroscopy to examine plasma from 4-month-old male Sprague-Dawley rats that were exposed to either air (n = 5) or 1 h Ecig exposure, after which blood samples were collected at varying times after exposure (i.e., 1-4, 24, 48 and 72 h postexposure, n = 4 or 5 in each time group). The EPR analyses were performed using the redox-sensitive hydroxylamine spin probe 1-hydroxy-3-carboxymethyl-2,2,5,5-tetramethyl-pyrrolidine (CMH) to measure the level of reactive oxidant species in the plasma samples. We found that EPR signal intensity from the CM • radical was significantly increased in plasma at 1-4, 24 and 48 h (P < 0.05, respectively) and returned to control (air) levels by 72 h. When evaluating the EPR results with MCA reactivity, we found a significant negative correlation (Pearson's P = 0.0027). These data indicate that impaired cerebrovascular reactivity resulting from vaping is associated with the oxidative stress level (measured by EPR from plasma) and indicate that a single 1 h vaping session can negatively influence vascular health for up to 3 days after vaping. HIGHLIGHTS: What is the central question of this study? Does the time course of oxidative stress triggered by electronic cigarette exposure follow the cerebral vascular dysfunction? What is the main finding and its importance? Electron paramagnetic resonance analysis shows that the oxidative stress induced after a single 1 h exposure to electronic cigarette aerosol takes ≤72 h to return to normal, which mirrors the time course for vascular dysfunction in the middle cerebral artery that we have reported previously., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Abstract: Sepsis causes dysfunction in different organs, but the pathophysiological mechanisms behind it are similar and mainly involve complex hemodynamic and cellular dysfunction. The importance of microcirculatory dysfunction in sepsis is becoming increasingly evident, in which endothelial dysfunction and glycocalyx degradation play a major role. This study aimed to investigate the effects of hydrogen-rich saline (HRS) on renal microcirculation in septic renal failure, and whether Sirt1 was involved in the renoprotective effects of HRS. Rats model of sepsis was established by cecal ligation and puncture, and septic rats were intraperitoneal injected with HRS (10 mL/kg). We found that in sepsis, the degree of glycocalyx shedding was directly proportional to the severity of sepsis. The seven-day survival rate of rats in the HRS+CLP group (70%) was higher than that of the CLP group (30%). HRS improved acidosis and renal function and reduced the release of inflammatory factors (TNF, IL-1β, and IL-6). The endothelial glycocalyx of capillaries in the HRS+CLP group (115 nm) was observed to be significantly thicker than that in the CLP group (44 nm) and EX527 (67.2 nm) groups by electron microscopy, and fewer glycocalyx metabolites (SDC-1, HS, HA, and MMP9) were found in the blood. Compared with the CLP group, HRS reduced renal apoptosis and upregulated Sirt1 expression, and inhibited the NF-κB/MMP9 signaling pathway. In addition, HRS did not damage immune function in septic rats as well. Generally speaking, our results suggest that HRS can alleviate the inflammatory response, inhibit glycocalyx shedding, improve septic kidney injury, and enhance survival rate., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (I SK1 - 3 ) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of I SK1 - 3 . H 2 O 2 enhanced I SK1 - 3 and ET-1 production. Enhancing I SK1 - 3 caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)