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Pulmonary hypertension (PH) often complicates chronic left-sided heart failure, with a remarkable impact on quality of life, exercise capacity, and survival. PH in chronic left-sided heart failure (PH-LHD) is not only caused by backward transmission of pressures but also involves impairment of atrial function, inflammation, and vasoconstriction. Once the left atrium loses its reservoir capacity, usually pulmonary vascular resistances increase. Right atrial dilation commonly represents the first sign of PH-LHD, before right ventricle dilatation and systolic dysfunction develop, leading to right heart insufficiency, and ultimately, right heart failure.

BACKGROUND: Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andeans with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andeans, to our knowledge, has not been investigated. If the interplay between iron status and pulmonary vascular tone in healthy Andeans remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude. RESEARCH QUESTION: Is the pulmonary vasculature in healthy Andeans responsive to iron infusion? STUDY DESIGN AND METHODS: In a double-blinded, block-randomized design, 24 healthy high-altitude Andeans and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [PIO(2)] of approximately 96 mm Hg) and during exaggerated hypoxia (PIO(2) of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion. RESULTS: Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg during exaggerated hypoxia (main effect, P < .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andeans than in the lowlanders (95% CI, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003). INTERPRETATION: The pulmonary vasculature of healthy Andeans and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS

Background and aim Yahom Navakot (YN), is a Thai traditional medicine, consisting of 54 plants, for treating fainting and dizziness. Thus, YN might relieve orthostatic hypotension (OH) symptoms, but its therapeutic action is unclear. Therefore, this study evaluated YN in OH rats, using a head-up tilt test (HUT). Experimental procedure Rats were anesthetized, and OH induced via a 90oHUT, before and after administering vehicle, a YN powder suspension (10, 100 mg/kg), a YN aqueous extract (100 mg/kg), and midodrine (5 mg/kg). The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), pulse pressure (PP) and heart rate (HR) were determined via the carotid artery. Plasma noradrenaline (NA) was evaluated. YN-induced vasoconstriction of isolated rat aorta rings was determined using organ bath technique. Results and conclusion Baseline BP increased with the 100 mg/kg YN powder suspension, the YN aqueous extract or midodrine, while HR decreased, compared with vehicle and control. 90oHUT rapidly reduced SBP, DPB and MAP, but increased HR, for control and vehicle-treated groups, but BP was steady with the 100 mg/kg YN powder suspension, the YN aqueous extract or midodrine. The 90oHUT-increase in HR was most pronounced with the 100 mg/kg YN powder suspension (the traditional formulation). This accords with increased plasma NA. YN also induced vasoconstriction in rat aorta via α1-receptor activation. Thus, the anti-hypotensive action of YN involved a stimulating effect on the heart and blood vessels via sympathetic activation. The results support the traditional use of YN and demonstrated the effectiveness of YN for OH prevention.

Background Inhibition of the microsomal prostaglandin (PG) E2 synthase (mPGES-1) introduces a promising anti-inflammatory treatment approach by specifically reducing PGE2 . The microvasculature is a central target organ for early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition in this vascular bed are of interest. Experimental approach The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (O100-400μm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses. Key results Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was not affected by the COX-2 inhibitors NS-398 and Etoricoxib or the COX-1/COX-2 inhibitor Indomethacin, tested in Non-ESKD controls. Correspondingly, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition only. In IL-1β treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockage of PGI2 signaling with an IP receptor antagonist did not restore the reduced constriction, neither did blocking of PGE2 -EP4 or signaling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nmol and constriction at μmol concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2 as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD. Conclusion Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 may be involved.

Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-L-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We generated a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

AIMS Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P

Central adiposity is associated with greater sympathetic support of blood pressure. β-adrenergic receptors (β-AR) buffer sympathetically mediated vasoconstriction and β-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized β-AR vasodilation would be lower in obese compared with normal weight adults. Because β-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to β-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1–12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18–40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [N(G)-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, β-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity. NEW & NOTEWORTHY We examined β-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, β-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Publisher Summary This chapter focuses on the effect of splanchnic circulation on overall circulatory function. The splanchnic circulation powerfully influences systemic arterial pressure via two distinct mechanisms. Widespread contraction of arteries in the splanchnic bed reduces blood flow to the region. Active constriction of veins in the splanchnic organs reduces regional blood volume. This has relatively little effect on total peripheral resistance but raises cardiac output and arterial pressure by increasing central blood volume and thus cardiac preload. Splanchnic sympathetic nerve activity (splSNA) is controlled by arterial and cardiopulmonary baroreceptors, and by inputs from other somatic and visceral afferents. Some stimuli are able to alter splSNA in a selective fashion. Impaired sympathetic splanchnic vasoconstriction is an important cause of orthostatic hypotension and other orthostatic disorders such as postural tachycardia syndrome. In portal hypertension there is a very marked increase in sympathetic nervous system activity, including to the splanchnic organs. During the development of arterial hypertension in humans, increased vascular resistance is observed first in the splanchnic circulation.

Sodium bicarbonate (NaHCOsub3/sub) is no longer recommended by the Neonatal Resuscitation Program (NRP), but is still being used by some neonatologists. The effects of NaHCOsub3/subon cerebral hemodynamics are unclear. Therefore, we investigated the effects of NaHCOsub3/subon cerebral blood flow (CBF) and cerebrovascular function using a newborn piglet model.Newborn pigs were anesthetized, intubated, and ventilated. Cranial windows were implanted to evaluate changes in pial arteriolar diameters (PADs) as a surrogate for CBF during a 4-h intravenous infusion of 3% NaHCOsub3/sub. Cerebrovascular reactivity to vasodilators and vasoconstrictors was investigated during vehicle control and during NaHCOsub3/subinfusion.NaHCOsub3/subinfusion caused significant and progressive pial arteriolar vasoconstrictions. During NaHCOsub3/subinfusion, cerebrovascular reactivity was preserved. Adding vasodilators decreased cerebral vasoconstriction, while adding vasoconstrictors exaggerated cerebral vasoconstriction.Intravenous infusion of NaHCOsub3/subover 4 h caused progressive vasoconstriction of pial arterioles. Cerebrovascular function evaluated by the responses of pial arterioles to physiologically relevant vasoconstrictors and vasodilators was preserved during NaHCOsub3/subinfusion. A notable additional reduction of PADs was observed during NaHCOsub3/subinfusion in the presence of vasoconstrictors. Extrapolating our findings to human neonates should alarm the clinicians that using NaHCOsub3/subin neonates may cause cerebral hypoperfusion.Cerebral vasoconstriction occurs during slow infusion of 3% diluted NaHCOsub3/sub. Cerebral vasoconstriction is exaggerated when another vasoconstrictor is added during NaHCOsub3/subinfusion. Cerebrovascular function is preserved during NaHCOsub3/subinfusion. Clinicians should be aware of the risk of cerebral hypoperfusion with NaHCOsub3/subinfusion in vulnerable neonates.

The article studies the indicators of renal tests in patients with diabetes mellitus (DM) type 2 associated with nonalcoholic fatty liver disease (NAFLD). It is found that NAFLD in patients with DM type 2 potentiates the development of diabetic nephropathy. Patients with DM type 2 and NAFLD have enhancement of tubular reabsorption, resulting from the violations in vasoconstriction/vasodilatation ratio. Urine creatinine can be considered a stable indicator of liver function test parameters and an early marker for progression of diabetic nephropathy in patients with type 2 DM and NAFLD.

Introduction and objectives The vasomotor function of new-generation drug-eluting stents designed to enhance stent healing and reendothelialization is unknown. This study aimed to compare the endothelial function of the infarct-related artery (IRA) treated with bioactive circulating endothelial progenitor cell-capturing sirolimus-eluting stents (COMBO) vs polymer-free biolimus-eluting stents (BioFreedom) in ST-segment elevation myocardial infarction patients at 6 months. Secondary objectives were to compare the microcirculatory function of the IRA and stent healing at 6 months. Methods Sixty patients were randomized to bioactive sirolimus-eluting stent vs polymer-free biolimus-eluting stents implantation. At 6 months, patients underwent coronary angiography with vasomotor, microcirculatory and optical coherence tomography examinations. Endothelial dysfunction of the distal coronary segment was defined as ≥ 4% vasoconstriction to intracoronary acetylcholine infusion. Results Endothelial dysfunction was similarly observed between groups (64.0% vs 62.5%, respectively; P = .913). Mean lumen diameter decreased by 16.0 ± 20.2% vs 16.1 ± 21.6% during acetylcholine infusion (P = .983). Microcirculatory function was similar in the 2 groups: coronary flow reserve was 3.23 ± 1.77 vs 3.23 ± 1.62 (P = .992) and the index of microcirculatory resistance was 24.8 ± 16.8 vs 21.3 ± 12.0 (P = .440). Optical coherence tomography findings were similar: uncovered struts (2.3% vs 3.2%; P = .466), malapposed struts (0.1% vs 0.3%; P = .519) and major evaginations (7.1% vs 5.6%; P = .708) were observed in few cases. Conclusions Endothelial dysfunction of the IRA was frequent and was similarly observed with new-generation drug-eluting stents designed to enhance stent reendothelialization at 6 months. Endothelial dysfunction was observed despite almost preserved microcirculatory function and complete stent coverage. Larger and clinically powered studies are needed to assess the role of residual endothelial dysfunction in ST-segment elevation myocardial infarction patients. Registered in ClinicalTrials.gov: NCT04202172

Aim: The cardio-ankle vascular index (CAVI) consists of intrinsic and functional arterial stiffness mainly regulated by vasoactive compounds. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was determined by applying the CAVI theory to the whole aorta and iliac-femoral arteries. We investigated the changes in aBeta and ifBeta in response to decreased blood pressure (BP) induced by the Ca 2＋ channel blocker nicardipine to elucidate the involvement of Ca 2＋ in aBeta and ifBeta. Methods: Pressure waves at the origin of the aorta (oA), distal end of the abdominal aorta (dA), and left femoral artery (fA) as well as flow waves at the oA were simultaneously recorded before and after the infusion of nicardipine (50 µg/kg/min) for 2 min in 12 male rabbits under pentobarbital anesthesia. Beta was calculated using the following formula: Beta=2ρ / PP×ln (SBP / DBP)×PWV 2 , where ρ, SBP, DBP, and PP denote blood density and systolic, diastolic, and pulse pressures, respectively. aBeta, ifBeta, and aortic-iliac-femoral Beta (aifBeta) were calculated using aPWV, ifPWV, and aifPWV, respectively. Results: SBP, mean arterial pressure (MAP), DBP, and total peripheral vascular resistance significantly decreased during the administration of nicardipine, whereas cardiac output significantly increased. aBeta and ifBeta significantly increased and decreased, respectively, whereas aifBeta did not change despite the decrease in BP. ifBeta and aBeta positively and negatively correlated with BP, respectively, whereas aifBeta did not correlate with SBP. Conclusions: There were contradictory arterial responses to nicardipine between the elastic and muscular arteries. Unknown vasoconstriction mechanisms that are not involved in Ca 2＋ influx may function in the aorta in response to decreased BP.

Background Cerebral blood flow (CBF) has direct impacts on the neuronal function and neurocognitive disorder. Oxidative stress from abdominal aortic surgery is important in the pathophysiology of CBF impairment. We investigated whether oxidative damage from abdominal aortic surgery is associated with reduced CBF and whether vascular endothelial dysfunction modifies these associations. Methods Rabbit closed cranial window preparation was used to measure changes in the pial arteriolar diameter after unclamping following abdominal aortic cross-clamping with an intravenous free radical scavenger, edaravone (control group, n=6; edaravone 10 μg/kg/min, n=6; 100 μg/kg/min, n=6). The pial vasodilatory responses to the topical application of acetylcholine (ACh) into the cranial window were investigated before abdominal aortic cross-clamping and after unclamping with the intravenous administration of edaravone (control group, n=6; edaravone 100 μg/kg/min, n=6). Results The aortic unclamping-induced vasoconstriction was significantly attenuated under the continuous infusion of edaravone at 100 μg/kg/min. The topical application of ACh after unclamping did not produce any changes in pial arteriolar responses in comparison to before aortic cross-clamping in the control or edaravone groups. The changes in the response to topical ACh after unclamping in the saline and edaravone groups did not differ to a statistically significant extent. Conclusions Free radicals during abdominal aortic surgery might have contracted cerebral blood vessels independently of the endothelial function in rabbits. The suppression of free radicals attenuated sustained pial arteriolar vasoconstriction after aortic unclamping. Thus, the free radical scavenger might have some brain protective effect that maintains the CBF independently of the endothelial function.

Endothelium-derived hyperpolarizing factor (EDHF) was envisaged as a chemical entity causing vasodilation by hyperpolarizing vascular smooth muscle (VSM) cells and distinct from nitric oxide (NO) ([aka endothelium-derived relaxing factor (EDRF)]) and prostacyclin. The search for an identity for EDHF unraveled the complexity of signaling within small arteries. Hyperpolarization originates within endothelial cells (ECs), spreading to the VSM by 2 branches, 1 chemical and 1 electrical, with the relative contribution varying with artery location, branch order, and prevailing profile of VSM activation. Chemical signals vary likewise and can involve potassium ion, lipid mediators, and hydrogen peroxide, whereas electrical signaling depends on physical contacts formed by homocellular and heterocellular (myoendothelial; MEJ) gap junctions, both able to conduct hyperpolarizing current. The discovery that chemical and electrical signals each arise within ECs resulted in an evolution of the single EDHF concept into the more inclusive, EDH signaling. Recognition of the importance of MEJs and particularly the fact they can support bidirectional signaling also informed the discovery that Ca2+ signals can pass from VSM to ECs during vasoconstriction. This signaling activates negative feedback mediated by NO and EDH forming a myoendothelial feedback circuit, which may also be responsible for basal or constitutive release of NO and EDH activity. The MEJs are housed in endothelial projections, and another spin-off from investigating EDH signaling was the discovery these fine structures contain clusters of signaling proteins to regulate both hyperpolarization and NO release. So, these tiny membrane bridges serve as a signaling superhighway or infobahn, which controls vasoreactivity by responding to signals flowing back and forth between the endothelium and VSM. By allowing bidirectional signaling, MEJs enable sinusoidal vasomotion, co-ordinated cycles of widespread vasoconstriction/vasodilation that optimize time-averaged blood flow. Cardiovascular disease disrupts EC signaling and as a result vasomotion changes to vasospasm.

The purpose of this literature review is to gain an overview of the role of platelet-activating factor (PAF) within each of the body systems and how it contributes to normal and pathophysiological states. The review showed that there are multiple functions of PAF that are common to several body systems; however, there is little evidence to explain why PAF has this affect across multiple systems. Interestingly, there seems to be conflicting research as to whether PAF is an overall protective or pathogenic pathway. Within this research, it was found that there are different pathways depending on the specific body system, as well as between body systems. However, one universal function reported in the literature is of PAF as a pro-inflammatory molecule. Overall, this review identified five major functions of PAF: vasoconstriction, increased inflammation, vascular remodeling, increased edema, and endothelial permeability.

This study presents electrical modelling of the arterial system to understand the effect of adrenaline on the aortae and small arteries in terms of their resistance and compliance. There is no categorical documentation in the current literature on the precise locations of arterial resistance (R) and compliance (C) in vasculature. Knowledge of their exact locations in the arterial tree enables re-assessment of the differential action of vasoactive drugs on resistance versus compliance vessels once we resolve beat-to-beat changes in R and C in response to these drugs. Isolated goat aortae and small arteries were perfused with a pulsatile pump and lumen pressures were recorded before and after addition of adrenaline. Equivalent electrical models were simulated, and biological data was compared against the electrical equivalents to derive interpretations. In the aortae, systolic pressure increased, diastolic pressure decreased, pulse pressure increased (P = .018); but the mean pressure remained the same (P = .357). Whereas in small artery, vasoconstriction caused an increase in systolic, diastolic, and mean pressures (P = .028). Simulations allow us to infer that vasoconstriction in the aorta leads to a reduction in compliance, but an increase in resistance if any, is not sufficient to alter the mean aortic pressure. Whereas vasoconstriction in small arteries increases resistance, but a decrease in compliance, if any, does not affect any of the pressure parameters measured. The presented study is first of its kind to give experimental evidence that large arteries and aorta are the only compliance vessels and small arteries are the only resistance vessels.

Mechanical stress from haemodynamic perturbations or interventional manipulation of epicardial coronary atherosclerotic plaques with inflammatory destabilization can release particulate debris, thrombotic material and soluble substances into the coronary circulation. The physical material obstructs the coronary microcirculation, whereas the soluble substances induce endothelial dysfunction and facilitate vasoconstriction. Coronary microvascular obstruction and dysfunction result in patchy microinfarcts accompanied by an inflammatory reaction, both of which contribute to progressive myocardial contractile dysfunction. In clinical studies, the benefit of protection devices to retrieve atherothrombotic debris during percutaneous coronary interventions has been modest, and the treatment of microembolization has mostly relied on antiplatelet and vasodilator agents. The past 25 years have witnessed a relative proportional increase in non-ST-segment elevation myocardial infarction in the presentation of acute coronary syndromes. An associated increase in the incidence of plaque erosion rather than rupture has also been recognized as a key mechanism in the past decade. We propose that coronary microembolization is a decisive link between plaque erosion at the culprit lesion and the manifestation of non-ST-segment elevation myocardial infarction. In this Review, we characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for prevention and treatment., In this Review, Kleinbongard and Heusch characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for the prevention and treatment of this phenomenon., Key points Coronary microembolization results from spontaneous or interventional erosion or rupture of an epicardial coronary atherosclerotic plaque.Atherothrombotic plaque debris causes physical obstruction of coronary microvessels and results in microinfarcts with an inflammatory response.The surviving myocardium around the patchy microinfarcts has reduced contractile function as a result of inflammatory signal transduction leading to myofibrillar oxidation.Atherosclerotic plaque erosion or rupture releases soluble substances that induce coronary microvascular endothelial dysfunction, vasoconstriction, platelet aggregation and coagulation.Routine use of interventional protection devices does not improve patient outcomes but these devices are indicated in cases of high atherothrombotic plaque burden.Plaque stabilization with statins and canakinumab prevents coronary microembolization, whereas platelet inhibitors, vasodilators and interleukin antagonists attenuate coronary microvascular impairment.

The imbalance of vasoconstrictor and vasodilator axes of the renin-angiotensin system (RAS) is observed in hypertension. Exercise regulates RAS level and improves vascular function. This study focused on the contribution of RAS axes in vascular function of mesenteric arteries and exercise-induced DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in hypertension. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were randomized into exercise or sedentary group. Levels of plasma RAS components, vascular tone, and DNA methylation markers were measured. Blood pressure of SHR was markedly reduced after 12 weeks of aerobic exercise. RAS peptides in plasma were all increased with an imbalanced upregulation of Ang II and Ang-(1–7) in SHR, exercise revised the level of RAS and increased Ang-(1–7)/Ang II. The vasoconstriction response induced by Ang II was mainly via type 1 receptors (AT1R), while this contraction was inhibited by Mas receptor (MasR). mRNA and protein of AT1R and MasR were both upregulated in SHR, whereas exercise significantly suppressed this imbalanced increase and increased MasR/AT1R ratio. Exercise hypermethylated Agtr1a and Mas1 genes, associating with increased DNMT1 and DNMT3b and SAM/SAH. Aerobic exercise ameliorates vascular function via hypermethylation of the Agtr1a and Mas1 genes and restores the vasoconstrictor and vasodilator axes balance.

Leukocyte extravasation into inflamed tissue is a complex process that is difficult to capture as a whole in vitro. We employed a blood-vessel-on-a-chip model in which endothelial cells were cultured in a tube-like lumen in a collagen-1 matrix. The vessels are leak-tight, creating a barrier for molecules and leukocytes. Addition of inflammatory cytokine TNF-α caused vasoconstriction, actin remodelling and upregulation of ICAM-1. Introducing leukocytes into the vessels allowed real-time visualisation of all different steps of the leukocyte transmigration cascade including migration into the extracellular matrix. Individual cell tracking over time distinguished striking differences in migratory behaviour between T-cells and neutrophils. Neutrophils cross the endothelial layer more efficiently than T-cells, but upon entering the matrix, neutrophils display high speed but low persistence, whereas T-cells migrate with low speed and rather linear migration. In conclusion, 3D imaging in real-time of leukocyte extravasation in a vessel-on-a-chip enables detailed qualitative and quantitative analysis of different stages of the full leukocyte extravasation process in a single assay.SummaryA functional hydrogel-based blood-vessel-on-a-chip model is used to study the complete leukocyte transendothelial migration process in real time. T-lymphocytes and neutrophils exhibit distinct migration dynamics in the extravascular matrix after transendothelial migration, which can be altered using a chemotactic gradient.

Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. Methods Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. Results mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P P P P P P Conclusions We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.

BACKGROUND/AIM This study investigated the effect of vascular endothelial growth factor (VEGF) inhibitor bevacuzimab (BVZ) on the rabbit basilar artery using an experimental subarachnoid hemorrhage (SAH) model. MATERIALS AND METHODS Eighteen adult male New-Zealand white rabbits were randomly divided into three groups: a control group (n=6), SAH group (n=6), and SAH+BVZ group (n=6). Experimental SAH was created by injecting autologous arterial blood into the cisterna magna. In the treatment group, the subjects were administered a daily dose of 10 mg/kg, intravenous BVZ 2 days after the SAH. Basilar artery diameters were measured with magnetic resonance angiography (MRA) 72 hours after the SAH in all groups. After 72 hours the animals? whole brains, including the upper cervical region, were obtained from all the animals after perfusion and fixation of the animal. The wall thickness, luminal area, and the apoptosis at the basilar arteries were evaluated in all groups. RESULTS BVZ significantly prevented SAH induced vasospasm confirmed in-vivo with MRA imaging with additional suppression of apoptosis on basilar artery wall. CONCLUSION VEGF inhibition with BVZ has shown to have a vasospasm and apoptosis attenuating effect on basilar artery in a SAH model.

Abnormal vasoconstriction, inflammation, and vascular remodeling can be promoted by angiotensin II (Ang II) in the renin-angiotensin system (RAS), leading to vascular dysfunction diseases such as hypertension and atherosclerosis. Researchers have recently focused on angiotensin I-converting enzyme inhibitory peptides (ACEIPs), that have desirable efficacy in vascular dysfunction therapy due to Ang II reduction by inhibiting ACE activity. Promising methods for the large-scale preparation of ACEIPs include selective enzymatic hydrolysis and microbial fermentation. Thus far, ACEIPs have been widely reported to be hydrolyzed from protein-rich sources, including animals, plants, and marine organisms, while many emerging microorganism-derived ACEIPs are theoretically biosynthesized through the nonribosomal peptide synthase (NRPS) pathway. Notably, vasodilatation, anti-inflammation, and vascular reconstruction reversal of ACEIPs are strongly correlated. However, the related molecular mechanisms underlying signal transduction regulation in vivo remain unclear. We provide a comprehensive update of the ACE-Ang II-G protein-coupled type 1 angiotensin receptor (AT1R) axis signaling and its functional significance for potential translation into therapeutic strategies, particularly targeting AT1R by ACEIPs, as well as specific related signaling pathways. Future studies are expected to verify the biosynthetic regulatory mechanism of ACEIPs via the NRPS pathway, the effect of gut microbiota metabolism on vascular dysfunction and rigorous studies of ACE-Ang II-AT1R signaling pathways mediated by ACEIPs in large animals and humans.

Recently, we demonstrated that chronic blockade of the renin-angiotensin system (RAS) lowered the blood pressure (BP) of adult Ren-2 transgenic rats (TGR) mainly through the attenuation of central sympathoexcitation. However, the participation of central and peripheral mechanisms in the development of high BP in immature TGR remains unclear. In the present study, 6-week-old heterozygous TGR males were chronically treated with intracerebroventricular (ICV) or intraperitoneal (IP) infusions of the AT1 receptor inhibitor losartan (1 or 2 mg/kg/day) for 4 weeks. The influence of these treatments on sympathetic- and angiotensin II-dependent BP components (BP response to pentolinium or captopril, respectively) as well as on BP response to exogenous angiotensin II were determined to evaluate the participation of central and peripheral RAS in hypertension development. Chronic IP losartan administration (1 or 2 mg/kg/day) lowered the BP of immature TGR by reducing both sympathetic and angiotensin II-dependent BP components. The central action of IP-administered losartan was indicated by a reduced BP response to acute ICV angiotensin II injection. Chronic ICV administration of a lower losartan dose (1 mg/kg/day) reduced only the sympathetic BP component, whereas a higher ICV administered dose (2 mg/kg/day) was required to influence the angiotensin II-dependent BP component. Accordingly, chronic ICV losartan administration of 2 mg/kg/day (but not 1 mg/kg/day) attenuated the BP response to acute intravenous angiotensin II application. In conclusion, central sympathoexcitation seems to play an important role in hypertension development in immature TGR. Central sympathoexcitation is highly susceptible to inhibition by low doses of RAS-blocking agents, whereas higher doses also affect peripheral angiotensin II-dependent vasoconstriction.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wildtype mice were treated with prazosin 12 h after CLP or nitric oxide synthase 2 (NOS-2) inhibitor, 30 min before and 6 and 12 h after CLP. In vivo experiments and biochemistry assays were performed 24 h after CLP. Sepsis decreased the systemic mean arterial pressure (MAP) and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decrease in GRK2 level associated with an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400 W. Treatment of non-septic mice with an NO donor reduced GRK2 content in the kidney. Therefore, our results show that an NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

Hydrogen sulfide (H 2 S) is an endogenous gaseous antioxidant and antihypertensive molecule produced during the homocysteine metabolism. MsrA (methionine sulfoxide reductase A) enables the metabolism of homocysteine by reducing methionine sulfoxide to methionine. Although HDAC (histone deacetylase) inhibition has been reported to show blood pressure lowering effects, their effects on endogenous H 2 S production are largely unknown. Here, we assessed the relevance of MsrA in high-fat diet (HFD)-induced hypertension and the effect of HDAC inhibition on MsrA expression, H 2 S production, and hypertension. Male C57BL/6 mice were fed a normal diet or HFD. HFD increased blood pressure and activities of HDAC3 and 6 but downregulated MsrA in the mesenteric arteries and the serum H 2 S level. HFD upregulated 4 hydroxynonenal, TNF (tumor necrosis factor)-α, and IL (interleukin)-6, and vasocontractile proteins. The histone H3 acetylation of the MsrA promoter was decreased by HFD. In hypertensive HFD-fed mice, administration of the HDAC inhibitor CG200745 lowered blood pressure and increased serum H 2 S level. CG200745 increased acetylation of histone H3 and MsrA levels in the mesenteric arteries while downregulating oxidative stress, inflammation, and vasocontractile proteins. Silencing of MsrA in the vascular smooth muscle cells recapitulated HFD-induced in vivo hypertensive effects. CG200745 increased the histone H3 acetylation of the MsrA promoter, MsrA expression, and H 2 S production in vascular smooth muscle cells, supporting the in vivo results. Collectively, HFD-induced downregulation of MsrA plays a pivotal role in HFD-induced hypertension by reducing H 2 S levels. MsrA expression is epigenetically regulated by HDAC inhibitors, providing HDAC inhibitors as a therapeutic option and MsrA and H 2 S as novel therapeutic targets. Graphic Abstract: An online graphic abstract is available for this article.

Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O2 from gestational day 4-21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETAR/ETBR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETBR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETBR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETBR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETBR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETBR/Nox1/4-derived ROS pathway.

Although vasodilatation evoked by acidosis at normal body temperature is well known, the reports regarding effect of acidosis on the reactivity of the isolated arteries at low temperatures are nonexistent. This study tested the hypothesis that the inhibitory effect of acidosis on the neurogenic vasoconstriction may be increased by cooling. Using wire myography, we recorded the neurogenic contraction of the rat tail artery segments to the electrical field stimulation in the absence and in the presence of 0.03–10.0 µmol/L noradrenaline. The experiments were conducted at 37 °C or 25 °C and pH 7.4 or 6.6 which was decreased by means of CO2. Noradrenaline at concentration of 0.03–0.1 µmol/L significantly potentiated the neurogenic vasoconstriction at 25 °C, and the potentiation was not inhibited by acidosis. Contrary to our hypothesis, acidosis at a low temperature did not affect the noradrenaline-induced tone and significantly increased the neurogenic contraction of the artery segments in the absence and presence of noradrenaline. These effects of acidosis were partly dependent on the endothelium and L-type Ca2+ channels activation. The phenomenon described for the first time might be of importance for the reduction in the heat loss by virtue of decrease in the subcutaneous blood flow at low ambient temperatures.

Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K+ channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na+ and Ca2+ , is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na+ influx contributes to PASMC Em regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K+ currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced Em depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1-/- ) prevents CH-induced Em depolarization and largely inhibits whole-cell NSCC currents, without affecting whole-cell K+ currents. Our results show a combination of factors, including inhibition of K+ efflux and augmented Na+ influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of Em in PASMCs during CH-induced pulmonary hypertension. KEY POINTS: In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well-established reduction of K+ conductance, we show that non-selective cation channel currents are increased and essential to the persistent Em depolarization in PASMCs following chronic hypoxia (CH)-induced pulmonary hypertension. The current study provides novel evidence that acid-sensing ion channel 1 (ASIC1)-mediated Na+ influx induces membrane depolarization and regulates Em in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.

Cardiovascular diseases (CVD) constitute the major cause of death worldwide and show a higher prevalence in the adult population. The human umbilical cord consistsof two arteries and one vein, both composed of three tunics. The tunica intima, lined with endothelial cells, regulates vascular tone through the production/release of vasoregulatory substances. These substances can be vasoactive factors released by endothelial cells (ECs) that cause vasodilation (NO, PGI2, EDHF, and Bradykinin) or vasoconstriction (ET1, TXA2, and Ang II) depending on the cell type (ECs or SMC) that reacts to the stimulus. Vascular studies using ECs are important for the analysis of cardiovascular diseases since endothelial dysfunction is an important CVD risk factor. In this paper, we will address the morphological characteristics of the human umbilical cord and its component vessels. the constitution of the vascular endothelium, and the evolution of human umbilical cord-derived endothelial cells when isolated. Moreover, the role played by the endothelium in the vasomotor tone regulation, and how it may be associated with the existence of CVD, were discussed.

Vascular endothelial growth factor-A (VEGF-A) is a master regulator of angiogenesis, with higher levels in infantile hemangioma (IH). The effects of propranolol on IH are not fully understood and may involve vasoconstriction, angiogenesis inhibition, and apoptosis induction. Therefore, we examined the effects of propranolol therapy on levels of VEGF-A in patients with IH in the proliferative phase and compared the VEGF-A levels to those in untreated patients in the involuting or involuted phases, as well as studied the consistency between the clinical and VEGF responses in patients receiving treatment. In a prospective study, we compared 24 patients with IH in the proliferative phase to 9 patients with IH in the involuting or involuted phase, assessing clinical responses to therapy and changes in VEGF-A levels after 3 months. The median VEGF level before treatment was 275 pg/ml; however, after 3 months, the level significantly decreased to 100 pg/ml (P = 0.007). Median VEGF was significantly higher in patients in the proliferative phase after 3 months of treatment (100 pg/ml) as compared to those in the involuting phase (50 pg/ml). We found no significant correlation between VEGF level and IH size reduction. Propranolol therapy induced a significant decline in VEGF levels at the 3-month evaluation in patients in the proliferative phase; however, this did not reach the levels of IH in the involuting phase. VEGF response was not translated to a clinical response in some patients with IH. These results put in uncertainty the clinical benefit of targeting VEGF pathway in IH.

Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by sustained elevated pulmonary arterial pressures in which the pulmonary vasculature undergoes significant structural and functional remodeling. To better understand disease mechanisms, in this review article we highlight recent insights into the regulation of pulmonary arterial cells by mechanical cues associated with PAH. Specifically, the mechanobiology of pulmonary arterial endothelial cells (PAECs), smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs) has been investigated in vivo, in vitro, and in silico. Increased pulmonary arterial pressure increases vessel wall stress and strain and endothelial fluid shear stress. These mechanical cues promote vasoconstriction and fibrosis that contribute further to hypertension and alter the mechanical milieu and regulation of pulmonary arterial cells.

The effects of 5/6 nephrectomy on contractile and dilatory properties of the superior mesenteric artery (SMA) and internal carotid artery (ICA) segments in spontaneously hypertensive rats (SHR) were studied under isometric conditions by wire myography. Subtotal 5/6 nephrectomy (5/6 Nx) in 3-month-old rats was taken as a chronic kidney disease model. Dilatation of phenylephrine-preconstricted arterial segments was elicited by acetylcholine (AСh) or sodium nitroprusside (SNP) in the absence and presence of potassium channel blockers (tetraethylammonium, glibenclamide) or a guanylyl cyclase inhibitor methylene blue. In 5/6 Nx vs. control rats, the phenylephrine-induced contractile response of the SMA was only slightly reduced, but significantly reduced in the presence of methylene blue. In the ICA of 5/6 Nx vs. control rats, this response was significantly weaker both in the absence and presence of the potassium channel blockers and guanylyl cyclase inhibitor. 5/6 nephrectomy had no effect on the dilatory response of both arteries to AСh or SNP, however, the contractile phase of the ICA response to AСh in the presence of glibenclamide significantly decreased in 5/6 Nx, but not in control, rats. It is concluded that chronic kidney disease may attenuate endothelium-dependent and independent vasoconstriction in SHR, to a greater extent in the ICA than SMA, as well as differently affect the signaling pathways of these responses in different types of arteries, involving ATP-sensitive potassium channels in the ICA and guanylyl cyclase in the SMA.

The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunction, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways.

Patients with diabetes are more susceptible to coronavirus disease 2019 (COVID-19), and as a consequence, develop more severe form of disease. This is partly due to a systemic inflammatory state and pro thrombotic milieu seen in metabolic syndrome. In this review, we attempt to explore the pathogenetic links between insulin resistance and COVID-19 disease severity. Insulin resistance is an underlying condition for metabolic syndromes, including type 2 diabetes, which impairs insulin signaling pathways affecting metabolic and cardiovascular homeostasis. A high concentration of circulating insulin shifts the balance to mitogen activated protein kinase (MAPK)-dependent signaling and causes endothelial cell damage. The phosphatidylinositol 3 kinase and MAPK dependent signaling pathways maintain a balance between nitric oxide-dependent vasodilator and endothelin-1 dependent vasoconstriction actions of insulin. Vascular smooth muscle cell dysfunction is responsible for inflammation and blood coagulation leading to microvascular and macrovascular complications in diabetes. Hyperactivity in renin-angiotensin system is implicated in development of islet oxidative stress and subsequent β-cell dysfunction, as it alters the islet blood flow. These deleterious effects of insulin resistance involving altered blood pressure, vascular dysfunction, and inflammation could be associated with increased severity in COVID-19 patients. We conclude that clinical and/or biochemical markers of insulin resistance should be included as prognostic markers in assessment of acute COVID-19 disease.

Pulmonary arterial hypertension is characterized by progressive pulmonary vascular remodeling and the eventual development of right heart failure. Multiple mechanisms are responsible, including vasoconstriction, metabolic flux, and inflammation. Since the early descriptions of pulmonary hypertension, female sex has been associated with increased prevalence of the disease, with research showing both detrimental and beneficial effects of estrogen and its metabolites. This article aims to describe how the female paradox arises from sex differences in pulmonary hypertension and how this has an impact on pathophysiology and future treatment.

Severe burns result in cardiovascular dysfunction, but responses in the peripheral vasculature are unclear. We hypothesize that severe burns disturb arterial contractility through acute changes in adrenergic and cholinergic receptor function. To address this, we investigated the changes in carotid artery contractility and relaxation following a severe burn. Thirty-four adult Sprague–Dawley male rats received a 40% total body surface area (TBSA) scald burn and fluid resuscitation using the Parkland formula. Control animals received sham burn procedure. Animals were serially euthanized between 6 h and 14 days after burn and endothelium-intact common carotid arteries were used for ex vivo force/relaxation measurements. At 6 h after burn, carotid arteries from burned animals demonstrated a > 50% decrease in cumulative dose-responses to norepinephrine (p −7 M angiotensin II (p p p

Background We tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1. Methods At birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain). Results Histopathology showed increased renal damage with 8–12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH. Conclusions Chronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.

Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca2+]i accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca2+ channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine’s effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO2) and neuronal [Ca2+]i, which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca2+]i accumulation and profoundly reduced tissue oxygenation (HbO2) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca2+]i accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca2+ channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine’s neurotoxicity in cocaine use disorders.

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4–L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Cleistanthus collinus leaf extracts are consumed for suicidal purposes in southern India. The boiled decoction is known to be more toxic than the fresh leaf juice. Although several compounds have been isolated and their toxicity tested, controversy remains as to which compounds are responsible for the high level of toxicity of C. collinus. We report herein that cleistanthoside A is the major toxin in the boiled aqueous extract of fresh leaves and causes death in rats in small doses. The toxicity of the boiled extract prepared in the manner described can be attributed entirely to cleistanthoside A. Cleistanthin A could also be isolated from the boiled extract, albeit in trace amounts. As hypotension not responding to vasoconstrictors is the cause of death in patients who have consumed the boiled extract, effects of cleistanthoside A on the determinants of blood pressure, namely, force of cardiac contraction and vascular resistance, were tested in isolated organ experiments. Cleistanthoside A has a direct vasoconstrictor effect; however, it inhibits ventricular contractility. Therefore, the notion that the shock in C. collinus poisoning is of vascular origin must be considered carefully, and the possibility of cardiogenic shock must be studied. We present the crystal structure of cleistanthin A and show the potency of fast NMR methods (NOAH4-BSCN-NUS) in the full spectral assignment of cleistanthoside A as a real-world sample of a natural product. We also compare the results of the NOAH4-BSCN-NUS NMR experiments with conventional NMR methods.

Loss of pressure-induced vasoconstriction increases susceptibility to renal and cerebral vascular injury. Favored paradigms underlying initiation of the response include transient receptor potential channels coupled to G protein-coupled receptors or integrins as transducers. Degenerin channels may also mediate the response. This review addresses the 1) evolutionary role of these molecules in mechanosensing, 2) limitations to identifying mechanosensitive molecules, and 3) paradigm shifting molecular model for a VSMC mechanosensor.

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α(1)-adrenergic vasoconstriction compared with combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6 women, 7 men) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP + ACh, SNP + ACh, and ATP + SNP, wherein the second dilator was coinfused after attaining steady state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48 ± 4; ACh: 57 ± 6; SNP: 53 ± 6 mL·min(−1)·100 mmHg(−1); P ≥ 0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP + ACh: 45 ± 9 vs. SNP + ACh: 18 ± 7 and ATP + SNP: 26 ± 4 mL·min(−1)·100 mmHg(−1), P < 0.05). Phenylephrine was subsequently infused to evaluate α(1)-adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh versus SNP (ΔFVC, −25 ± 3 and −29 ± 4 vs. −48 ± 3%; P < 0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP + ACh (−13 ± 3%; P < 0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP + ACh: −26 ± 3%; ATP + SNP: −31 ± 4%; both P < 0.05 vs. ATP + ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α(1)-adrenergic vasoconstriction in humans. NEW & NOTEWORTHY The results of this study highlight the vascular endothelium as a critical site for integration of vasomotor signals in humans. To our knowledge, this is the first study to demonstrate that combined stimulation of the endothelium with ATP and ACh results in enhanced vasodilation compared with combination of either ATP or ACh with an endothelium-independent dilator. Furthermore, we show that ATP and ACh interact to modulate α(1)-adrenergic vasoconstriction in human skeletal muscle in vivo.

Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by excessive proliferation and vasoconstriction of small pulmonary artery vascular smooth muscle cells (PASMCs). Coptidis rhizoma (CR) because of the complexity of the components, the underlying pharmacological role and mechanism of it on PAH remains unknown. In this article, the network pharmacological analysis was used to screen the main active constituents of CR and the molecular targets that these constituents act on. Then, we evaluated the importance of berberine and quercetin (biologically active components of CR) on the proliferation and migration of PASMCs and vascular remodeling in experimental models of PAH. Our results showed that berberine and quercetin effectively inhibited the proliferation and migration of hypoxia-induced PASMCs in a manner likely to be mediated by the suppression of MAPK1, NADPH oxidase 4 (NOX4), and cytochrome P450 1B1 (CYP1B1) expression. Furthermore, berberine and quercetin treatment attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension in rat models. In conclusion, this research demonstrates CR might be a promising treatment option for PAH, and the network pharmacology approach can be an effective tool to reveal the potential mechanisms of Chinese herbal medicine.

F2-Isoprostanes (F2-IsoPs) and Isofurans (IsoF), specific markers of lipid peroxidation in vivo, have been reported to be elevated and have prognostic implications following subarachnoid hemorrhage (SAH). Platelet activation and vasoconstriction are attributed to these compounds. Elevated IsoF to F2-IsoPs ratios have been proposed as in vivo biomarkers of mitochondrial dysfunction. In this pilot study, we examined their performance as specific biomarkers for delayed cerebral ischemia (DCI) development following SAH. Eighteen patients with SAH and six controls with normal neuroimaging and cerebrospinal fluid (CSF) analysis results underwent CSF sampling and abstraction of clinical, demographic, and laboratory data. Samples (two) of CSF were collected on day 1 and once on days 5–8 post bleed. F2-IsoP and IsoF assays were performed by gas chromatography/mass spectroscopy methods. Levels are expressed in median (interquartile range) for nonnormally distributed data. Repeated sample measurements were compared using the Wilcoxon signed-rank test, whereas the Mann–Whitney U-test was used for other nonnormally distributed data. Mean age was 61 ± 15.7 (SAH cases) versus 48 ± 10 (controls) years, and 80% of patients with SAH were women. Median Hunt and Hess score was 3 (2–4), and modified Fisher scale was 3 (3–4). Thirty nine percent of patients developed DCI. F2-IsoP were significantly higher in SAH cases than in controls [47.5 (30.2–53.5) vs. 26.0 (21.2–34.5) pg/mL]. No significant differences were observed in patients with or without DCI [41 (33.5–52) vs. 44 (28.5–55.5) pg/mL]. IsoF were elevated in the second CSF sample in nine patients but were undetectable in the remainder cases and all controls. Patients who developed DCI had significantly higher IsoF than those who did not [57 (34–72) vs. 0 (0–34) pg/mL]. Patients who met criteria for DCI had a significantly higher IsoF to F2IsoPs ratio on the late CSF sample [1.03 (1–1.38) vs. 0 (0–0.52)]. Preliminary findings from this study suggest that IsoF may represent a specific biomarker predicting DCI following SAH. Future studies to further explore the value of IsoF as biomarkers of secondary brain injury following SAH seem warranted.

A growing body of evidence supports the premise that deficiencies of zinc and angiotensin-converting enzyme 2 (ACE2, a zinc enzyme) determine severity of coronavirus disease 2019 (COVID-19). ACE2 is part of the renin–angiotensin system (RAS) and acts as a feedback control system moderating blood pressure, keeping blood pressure within normal limits. For a virus to infect a person, the virus has to get inside the person’s cells. The virus that causes COVID-19 uses ACE2 to get into the cell. Think of this like an invader from outer space attacking your car by getting in through your cruise control; the RAS is like the cruise control of your car. What happens next depends on how robust your cruise control is. If your cruise control is young and healthy perhaps very little happens; your car may slow down or speed up a bit. But if your cruise control is in poor condition the attack might disrupt the entire speed control system; your car may brake suddenly or speed out of control and crash. Feedback control systems (natural or man-made) are designed to keep dynamic systems in control, but under certain situations can drive the system completely out of control. The RAS is composed of two feedback loops: the ACE loop provides amplification, increasing pro-inflammatory cytokines and blood pressure; the ACE2 loop provides fine control and mitigates the vasoconstrictive, pro-inflammatory, and thrombotic actions of the ACE loop. Usually, there is balance, but in the setting of COVID-19, underlying deficiencies of zinc and ACE2 can lead to an imbalance. Exacerbated by the severe downregulation of ACE2 seen with viral entry, a “tipping point” is reached with loss of control of the RAS system resulting in increased angiotensin II (Ang II) causing downstream vasoconstriction, inflammation, and thromboses. These, in turn, lead to complications often seen in “severe COVID-19” such as acute respiratory distress syndrome (ARDS) or cytokine storm, often seen in high-risk patients in the second week of illness. This model suggests that supplemental zinc could replenish zinc in ACE2, stabilize the ACE2 axis, and prevent disruption of the RAS. This would prevent the vasoconstrictive, inflammatory, and thrombotic actions of Ang II, thus preventing the severe COVID-19 complications which cause the high morbidity and mortality seen in high-risk patients with underlying zinc deficiency. Zinc supplements are available, easy to use, and relatively safe. Randomized clinical trials are needed to confirm safety and efficacy of zinc supplementation to decrease severity of and morality from COVID-19 in high-risk patients. Since replenishment of zinc and active ACE2 in patients in whom these are deficient may take weeks, supplementation in high-risk populations prior to COVID infection may be required. Such supplementation should not replace vaccination but may be useful in populations for whom vaccination is not available or for populations exposed to viral variants to which available vaccines have insufficient coverage.

Reversible cerebral vasoconstriction syndrome (RCVS) is a clinicoradiological syndrome characterized by segmental vasoconstriction of cerebral arteries with resolution in most patients within 1 to 3 months. It has been known to be a benign uniphasic reversible illness but cases of fulminant RCVS with mortality have also been reported. The symptoms can be varied with presentations like transient ischemic attack (TIA), ischemic stroke (IS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and posterior reversible encephalopathy syndrome (PRES). We report a postpartum female with RCVS with radiological features of ICH, SAH, atypical PRES, and atypical clinical presentation as well. RCVS can be frequently missed unless there is a high index of suspicion. Hence clinicians should be aware of the typical and the atypical presentation of RCVS along with the radiological findings with the potential complications. Early suspicion and detection in the emergency help in recovery and reducing morbidity.

Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg−1·h−1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of