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BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

INTRODUCTION: Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development. METHODS: We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia. RESULTS: Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCIIhiCCR2+EAR2+ cells characterized the acute inflammatory phase, while TLF+VCAM1hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways. DISCUSSION: Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension.

Kawasaki disease (KD) causes vascular injury and lifelong remodeling. Excessive intimal proliferation has been observed, resulting in coronary artery lesions (CALs). However, the mechanisms underlying vascular remodeling in CAL and statin treatment have not been comprehensively elucidated. This study aimed to investigate the effects of statins on vascular remodeling using a KD mouse model. Candida albicans water‐soluble substance (CAWS) was intraperitoneally injected in 5‐week‐old male apolipoprotein‐E‐deficient mice. They were categorized as follows (n = 4): control, CAWS, CAWS+statin, and late‐statin groups. The mice were euthanized at 6 or 10 weeks after injection. Statins (atorvastatin) were initiated after CAWS injection, except for the late‐statin group, for which statins were internally administered 6 weeks after injection. Elastica van Gieson staining and immunostaining were performed for evaluation. Statins substantially suppressed the marked neointimal hyperplasia induced by CAWS. Additionally, CAWS induced TGFβ receptor II and MAC‐2 expression around the coronary arteries, which was suppressed by the statins. KD‐like vasculitis might promote the formation of aneurysm by destroying elastic laminae and inducing vascular stenosis by neointimal proliferation. The anti‐inflammatory effects of statins might inhibit neointimal proliferation. Therefore, statin therapy might be effective in adult patients with KD with CAL by inhibiting vascular remodeling. [ABSTRACT FROM AUTHOR]

A role for metabolically active adipose tissue in pulmonary hypertension (PH) pathogenesis is emerging. Alterations in cellular metabolism in metabolic syndrome are triggers of PH‐related vascular dysfunction. Metabolic reprogramming in proliferative pulmonary vascular cells causes a metabolic switch from oxidative phosphorylation to glycolysis. PDE3A and PDE3B subtypes in the regulation of metabolism in pulmonary artery smooth muscle cells (PASMC) are poorly understood. We previously found that PDE3A modulates the cellular energy sensor, AMPK, in human PASMC. We demonstrate that global Pde3a knockout mice have right ventricular (RV) hypertrophy, elevated RV systolic pressures, and metabolic dysfunction with elevated serum free fatty acids (FFA). Therefore, we sought to delineate Pde3a/Pde3b regulation of metabolic pathways in PASMC. We found that PASMC Pde3a deficiency, and to a lesser extent Pde3b deficiency, downregulates AMPK, CREB and PPARγ, and upregulates pyruvate kinase dehydrogenase expression, suggesting decreased oxidative phosphorylation. Interestingly, siRNA Pde3a knockdown in adipocytes led to elevated FFA secretion. Furthermore, PASMC exposed to siPDE3A‐transfected adipocyte media led to decreased α‐SMA, AMPK and CREB phosphorylation, and greater viable cell numbers compared to controls under the same conditions. These data demonstrate that deficiencies of Pde3a and Pde3b alter pathways that affect cell growth and metabolism in PASMC. [ABSTRACT FROM AUTHOR]

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage. Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging. [ABSTRACT FROM AUTHOR]

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Background: Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear. Methods and results: In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models. Conclusions: Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH. Highlights: (1) Que can significantly improve the hemodynamic changes, RVH and pulmonary vascular remodeling in MCT induced PAH rats. (2) Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by regulating TGF-β1/Smad2/Smad3 pathway, thus playing a protective role in PAH pulmonary vascular remodeling. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor–vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease's different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost. [ABSTRACT FROM AUTHOR]

Hemolysis is associated with pulmonary hypertension (PH), but the direct contribution of circulating free heme to the PH pathogenesis remains unclear. Here, we show that the elevated levels of circulating free heme are sufficient to induce PH and inflammatory response in mice and confirm the critical role of mitogen-activated protein kinase kinase-3 (MKK3)-mediated pathway in free heme signaling. Following the continuous infusion of heme for 2 wk, wild-type (WT) but not MKK3 knockout (KO) mice develop PH, as evidenced by a significantly elevated right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling. The MKK3/p38 axis, markedly activated by heme infusion in WTs, results in upregulated proliferative/cytokine signaling targets Akt, ERK1/2, and STAT3, which were abrogated in MKK3 KO mice. Moreover, the MKK3 KOs were protected against heme-mediated endothelial barrier dysfunction by restoring the tight junction protein zonula occludens-1 expression and diminishing the inflammatory cell infiltration in the lungs. Plasma cytokine multiplex analysis revealed a severe cytokine storm already 24 h after initiation of heme infusion, with a significant increase of 19 cytokines, including IL-1b, IL-2, IL-6, IL-9, and TNF-a, in WT animals and complete attenuation of cytokine production in MKK3 KO mice. Together, these findings reveal a causative role of circulating free heme in PH through activating inflammatory and proliferative responses. The central role of MKK3 in orchestrating the heme-mediated pathogenic response supports MKK3 as an attractive therapeutic target for PH and other lung inflammatory diseases linked to hemolytic anemia. NEW & NOTEWORTHY: This study demonstrates that elevated levels of circulating free heme can induce pulmonary hypertension (PH) and inflammation in mice. Continuous heme infusion activated the MKK3/p38 pathway, leading to increased right ventricular pressure, right ventricular hypertrophy, and vascular remodeling. This activation upregulated signaling cascades such as Akt, ERK1/2, and STAT3, whereas MKK3 knockout mice were protected against these changes and had reduced inflammatory responses, highlighting MKK3's potential as a therapeutic target for PH. [ABSTRACT FROM AUTHOR]

Aims: Endothelial cells are the critical targets of injury in diabetic nephropathy (DN), and endothelial cell lesions contribute to the disease progression. Neurite outgrowth inhibitor B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, plays a pivotal role in vascular remodeling after injury, and maintains the structure and function of the ER. Yet, the role of Nogo-B in the regulation of ER stress and endothelial cell injury remains largely unknown. Herein, we tested the hypothesis that Nogo-B activates ER stress-mediated autophagy and protects endothelial cells in DN. Results: The level of Nogo-B was decreased in glomerular endothelial cells in biopsy specimens from DN patients. In vivo and in vitro studies have shown that silencing Nogo-B activated ER stress signaling, and affected the expression of autophagy-related marker early growth response 1 and microtubule-associated protein light chain 3 (LC3) in endothelial cells in hyperglycemic condition. Conclusion and Innovation: These results denote that Nogo-B contributes to ER stress-mediated autophagy and protects endothelial cells in DN, providing new evidence for understanding the role of ER stress-mediated autophagy in endothelial cells of DN. [ABSTRACT FROM AUTHOR]

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label‐free quantitative proteomic analysis, western blotting, and RT‐PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does recombinant Lactobacillus expressing granulocyte colony-stimulating factor (G-CSF) have a better protective effect than the current treatment of thin endometrium (TE)? SUMMARY ANSWER This study suggested that the intrauterine injection of Lactobacillus crispastus (L. crispastus)-pPG612-G-CSF has a positive effect on preventing TE induced by 95% alcohol in mice. WHAT IS KNOWN ALREADY TE has a negative impact on the success rate of ART in patients, and is usually caused by intrauterine surgery, endometrial infection, or hormone drugs. Exogenous G-CSF can promote endometrial vascular remodelling and increase endometrial receptivity and the embryo implantation rate. Moreover, Lactobacillus plays a crucial role in maintaining and regulating the local microecological balance of the reproductive tract, and it could be a delivery carrier of the endometrial repair drug G-CSF. STUDY DESIGN, SIZE, DURATION We constructed engineered L. crispastus strains expressing G-CSF. The mice were divided into five groups: (i) Control group (C, n = 28), uteri were treated with preheated saline solution via intrauterine injection on the third and sixth day of oestrus; (ii) Model group (M, n = 35), where uteri were treated with 95% alcohol on the third day of oestrus and preheated saline solution on the sixth day of oestrus via intrauterine injection; (iii) L. crispatus -pPG612-treatment group (L, n = 45), where uteri were treated with 95% alcohol on the third day of oestrus and 0.1 ml × 108 CFU/ml L. crispatus -pPG612 on the sixth day of oestrus via intrauterine injection; (iv) L. crispatus -pPG612-treatment group (LG, n = 45), where uteri were treated with 95% alcohol on the third day of oestrus and 0.1 ml × 108 CFU/ml L. crispatus -pPG612-G-CSF on the sixth day of oestrus via intrauterine injection; (v) G-CSF-treatment group (G, n = 52), where uteri were treated with 95% alcohol on the third day of oestrus and 30 µg/kg G-CSF on the sixth day of oestrus via intrauterine injection. Then, we compared the effects of L. crispastus , L. crispatus -pPG612-G-CSF and G-CSF on endometrial thickness, angiogenesis, fibrosis, and inflammation in the TE mouse. PARTICIPANTS/MATERIALS, SETTING, METHODS We collected uterine tissues for haematoxylin–eosin staining, immunohistochemical staining, Western blot and RT–PCR, as well as serum for ELISA and uterine flushing solution for high-throughput sequencing. MAIN RESULTS AND THE ROLE OF CHANCE Compared with those in the M group (the mice of the group were intrauterine injected 95% alcohol and treated with saline solution), the L. crispatus -pPG612-G-CSF strain increased the thickness of the endometrium (P  <   0.001) and the number of blood vessels and glands (both P  <   0.001), enhanced the expression of cytokeratin 19 (CK19) (P  <   0.001), vimentin (Vim) (P  <   0.001), vascular endothelial growth factor-A (P  <   0.001), and CD34 (P  <   0.001), and decreased fibrosis levels (P  =   0.004). In addition, the high-throughput sequencing results indicated that the L. crispatus -pPG612-G-CSF strain could decrease the abundance of Pseudomonas (P  =   0.044) and Actinomyces spp. (P  =   0.094) in TE mice and increased the average number of embryos (P  =   0.036). Finally, the L. crispatus -pPG612-G-CSF strain was preliminarily confirmed to activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway and enhance the mRNA expression of hypoxia-inducible factor-1α (P  <   0.001), vascular endometrial growth factor (P  =   0.003), and endothelial cell nitric oxide synthase (P  =   0.003) in mouse uterine tissue. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Therapy with the L. crispatus -pPG612-G-CSF strain has tremendous potential to accelerate the reparative processes of TE. However, we have reported only the expression of genes and proteins related to the PI3K/AKT pathway, and numerous other mechanisms may also be involved in the restoration of the endometrium by L. crispatus -pPG612-G-CSF. WIDER IMPLICATIONS OF THE FINDINGS The results from the study provide new ideas and suggest new methods for TE treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was financially supported by the Project of Science and Technology Development Plan of Jilin Province (grant number 20210101232JC), the Science and Technology Plan Item of Jilin Provincial Education Department (grant number JT53101022010), and the Doctoral Research Start-up Fund of Jilin Medical University (grant numbers JYBS2021014LK and 2022JYBS006KJ). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. [ABSTRACT FROM AUTHOR]

The mechanism behind hemodialysis arteriovenous fistula (AVF) failure remains poorly understood, despite previous efforts to correlate altered hemodynamics with vascular remodeling. We have recently demonstrated that transitional flow induces high-frequency vibrations in the AVF wall, albeit with a simplified model. This study addresses the key limitations of our original fluid–structure interaction (FSI) approach, aiming to evaluate the vibration response using a more realistic model. A 3D AVF geometry was generated from contrast-free MRI and high-fidelity FSI simulations were performed. Patient-specific inflow and pressure were incorporated, and a three-term Mooney–Rivlin model was fitted using experimental data. The viscoelastic effect of perivascular tissue was modeled with Robin boundary conditions. Prescribing pulsatile inflow and pressure resulted in a substantial increase in vein displacement ( + 400 %) and strain ( + 317 %), with a higher maximum spectral frequency becoming visible above -42 dB (from 200 to 500 Hz). Transitioning from Saint Venant–Kirchhoff to Mooney–Rivlin model led to displacement amplitudes exceeding 10 micrometers and had a substantial impact on strain ( + 116 %). Robin boundary conditions significantly damped high-frequency displacement ( - 60 %). Incorporating venous tissue properties increased vibrations by 91%, extending up to 700 Hz, with a maximum strain of 0.158. Notably, our results show localized, high levels of vibration at the inner curvature of the vein, a site known for experiencing pronounced remodeling. Our findings, consistent with experimental and clinical reports of bruits and thrills, underscore the significance of incorporating physiologically plausible modeling approaches to investigate the role of wall vibrations in AVF remodeling and failure. [ABSTRACT FROM AUTHOR]

Pulmonary artery stenosis (PAS) often presents in children with congenital heart disease, altering blood flow and pressure during critical periods of growth and development. Variability in stenosis onset, duration, and severity result in variable growth and remodeling of the pulmonary vasculature. Computational fluid dynamics (CFD) models enable investigation into the hemodynamic impact and altered mechanics associated with PAS. In this study, a one-dimensional (1D) fluid dynamics model was used to simulate hemodynamics throughout the pulmonary arteries of individual animals. The geometry of the large pulmonary arteries was prescribed by animal-specific imaging, whereas the distal vasculature was simulated by a three-element Windkessel model at each terminal vessel outlet. Remodeling of the pulmonary vasculature, which cannot be measured in vivo, was estimated via model-fitted parameters. The large artery stiffness was significantly higher on the left side of the vasculature in the left pulmonary artery (LPA) stenosis group, but neither side differed from the sham group. The sham group exhibited a balanced distribution of total distal vascular resistance, whereas the left side was generally larger in the LPA stenosis group, with no significant differences between groups. In contrast, the peripheral compliance on the right side of the LPA stenosis group was significantly greater than the corresponding side of the sham group. Further analysis indicated the underperfused distal vasculature likely moderately decreased in radius with little change in stiffness given the increase in thickness observed with histology. Ultimately, our model enables greater understanding of pulmonary arterial adaptation due to LPA stenosis and has potential for use as a tool to noninvasively estimate remodeling of the pulmonary vasculature. [ABSTRACT FROM AUTHOR]

Purpose: To document vascular changes in eyes with post-fever retinitis (PFR) pre and post treatment demonstrated using optical coherence tomography angiography (OCTA). Methods: This is a retrospective observational case series wherein patients with PFR were retrospectively evaluated for changes in the retinal vasculature during the course of disease using OCTA. Results: At presentation, OCTA revealed flow void areas in superficial and deep capillary plexus (SCP and DCP) corresponding to the areas of retinitis. Post treatment, OCTA showed a significant decrease in the flow void areas with the appearance of new capillary network in both SCP and DCP. The optical coherence tomography also demonstrated normalization of retinal architecture over time. It is speculated that the good visual outcome in PFR could be attributed to the normalization of retinal architecture and remodelling in retinal vasculature. Conclusion: OCTA being non-invasive can be used to understand and quantify the extent of vascular remodelling in PFR. [ABSTRACT FROM AUTHOR]

Background: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage and a more hemorrhagic disease course compared to women. In this cohort study, we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. Methods: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo magnetic resonance imaging (MRI) markers and local cortical iron burden and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodeling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. Results: In 6120 individuals from the NACC database (45% women, mean age 80 years), the presence of parenchymal amyloid-β (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53–0.88)) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75 years), a lower microbleed count (p < 0.001) but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p < 0.001) compared to women. CAA percentage area was comparable in men and women (p = 0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p = 0.03). Conclusion: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodeling, may contribute, but future studies are necessary to replicate our findings in larger data sets and to further investigate the underlying mechanisms behind these complex sex differences. [ABSTRACT FROM AUTHOR]

Objective: This study aims to comprehensively analyze a multiple-marker panel consisting of 55 morphofunctional and biochemical markers in 123 patients diagnosed with non-ST-segment elevation myocardial infarction (NSTEMI). The goal of this study was to identify novel pathogenetic landmarks and diagnostic predictors associated with NSTEMI. Methods: The study includes 123 patients diagnosed with NSTEMI based on ESC Guidelines criteria. Clinical characteristics, morphofunctional markers, and serum levels of 53 biochemical markers related to inflammation, oxidative stress, endothelial dysfunction, cellular injury, hemostasis, and myocardial remodeling were assessed. A control group of 47 healthy individuals was included for comparison. Results: NSTEMI patients exhibited an activated inflammatory status, oxidative stress, and endothelial dysfunction. Notable increases in inflammation markers, alterations in adipokines, and changes in oxidative stress markers were observed. Endothelial dysfunction markers indicated vascular remodeling and dysfunction. Cellular injury markers, including cMyBP-C, suggested myocardial necrotic injury. Hemostasis markers showed impaired anticoagulant systems, and ECM remodeling markers indicated increased matrix metalloproteinases. Conclusion: The multiple-marker panel provides insights into novel pathogenetic entities associated with NSTEMI. Markers such as MPO, MMP-8, E-selectin, PhA2, Ang 2, FE, MF, and cMyBP-C demonstrate potential diagnostic and prognostic value. This comprehensive analysis enhances our understanding of NSTEMI pathogenesis and offers potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Purpose: Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare vascular disease, the treatment strategies for which remain debated. This retrospective study aimed to compare the outcomes of conservative and endovascular treatments in patients with SISMAD. Materials and Methods: Fifty-eight patients with SISMAD confirmed by computed tomography angiography admitted to our hospital between November 2017 and May 2021 and received confirmed conservative (n=43) or endovascular (n=15) treatment. The patient demographics, imaging analysis, and follow-up results were analyzed and compared. Results: The cohort included 54 males and 4 females with a mean age of 52 years. Abdominal pain was the major complaint (49/58, 84.5%), followed by chest pain (2/58, 3.4%). The mean follow-up was 9.1±7.9 months. The 2 main Sakamoto types were type III (27/58, 46.6%) and type IV (16/58, 27.6%). Most patients in both groups had angle 1 (aortomesenteric angle) and angle 2 (superior mesenteric artery [SMA] course) of over 80°. About 67.3% of patients had long length of dissection (>60 mm). The median distance between the SMA root and the dissection entry site was 1.5 cm, mostly (84.5% of the patients) in the curved segment of the SMA. Telephone follow-ups found that most patients survived pain-free, and none underwent intestinal resection. Only 4 patients, 2 in each group, had recurrent abdominal pain during follow-up and received stenting treatment to achieve complete vascular remodeling. Importantly, we found that the conservative and endovascular therapies achieved similar high remodeling rates (94% and 100%, respectively; p=0.335). The conservative group achieved satisfying vascular remodeling (partial, 35%; complete, 59%), making it as safe and effective a treatment as endovascular therapy. Conclusions: Initial conservative management is safe and effective in patients with SISMAD. A high technical success rate and favorable short-term outcomes were associated with endovascular procedures as secondary interventions. It would be helpful to conduct large-scale, prospective, randomized controlled trials with long-term follow-up for SISMAD. Clinical Impact: 1. This research provided more detail clinical information, such as evaluation of abdominal pain and measurements of SMA angles, which is all relevant to treatment. 2. What's more, the most surprising results of follow-up part shown that conservative treatment could reached the remodeling rate as high as endovascular treatment, which was relatively low in other studies. It helps us share our treatment experience with clinicians. 3. In addition, we get limited knowledge about this rare disease, it's encouraging us to do more researches based on the results we had. [ABSTRACT FROM AUTHOR]

We investigate the influence of scleral cautery during cataract surgery on limbal vascular density and remodeling using anterior segment optical coherence tomography angiography (AS-OCTA). Twenty eyes of 20 patients who underwent cataract surgery with a sclerocorneal incision were included. Patients were divided into two groups: non-cautery (n = 10) and cautery (n = 10). The area around the incision site was scanned using AS-OCTA before surgery and at 1, 3, 5, 7, 14, 21, 28, and 90 days postoperatively. Images were analyzed to depict conjunctival vasculature (surface to a depth of 200 μm) and intrascleral vasculature (depth of 200 to 1000 μm). Vascular density was evaluated using ImageJ software. In the non-cautery group, intrascleral vascular density significantly increased during the wound-healing period up to 21 days postoperatively. Cautery application completely diminished this effect, resulting in significantly reduced intrascleral vascular density in the cautery group compared to the non-cautery group until 5 days after surgery. On the seventh day and later, intrascleral vascular density in the cautery group recovered, but the vascular pattern did not return to its preoperative state even at 90 days after surgery. Conjunctival flap vascular density was reduced for 28 days after surgery, with cautery application further decreasing conjunctival vascular density. AS-OCTA enabled separate observation of conjunctival and intrascleral vasculature. Intrascleral blood flow significantly increased after cataract surgery, but scleral cauterization markedly blocked this effect. The vascular reconstruction process following cataract surgery continued for almost a month, with cautery application leading to prolonged vascular disruption and altered vascular patterns. [ABSTRACT FROM AUTHOR]

Background: As one of the most common traffic-related pollutants, diesel exhaust (DE) confers high risk for cardiovascular and respiratory diseases. However, its impact on pulmonary vessels is still unclear. Methods: To explore the effects of DE exposure on pulmonary vascular remodeling, our study analyzed the number and volume of small pulmonary vessels in the diesel engine testers (the DET group) from Luoyang Diesel Engine Factory and the controls (the non-DET group) from the local water company, using spirometry and carbon content in airway macrophage (CCAM) in sputum. And then we constructed a rat model of chronic DE exposure, in which 12 rats were divided into the DE group (6 rats with 16-week DE exposure) and the control group (6 rats with 16-week clean air exposure). During right heart catheterization, right ventricular systolic pressure (RVSP) was assessed by manometry. Macrophage migration inhibitory factor (MIF) in lung tissues and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA, respectively. Histopathological analysis for cardiovascular remodeling was also performed. Results: In DET cohort, the number and volume of small pulmonary vessels in CT were positively correlated with CCAM in sputum (P<0.05). Rat model revealed that chronic DE-exposed rats had elevated RVSP, along with increased wall thickness of pulmonary small vessels and right the ventricle. What's more, the MIF levels in BALF and lung tissues were higher in DE-exposed rats than the controls. Conclusion: Apart from airway remodeling, DE also induces pulmonary vascular remodeling, which will lead to cardiopulmonary dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Even under the standard medical care, patients with left ventricular (LV) failure or heart failure (HF) often progress to pulmonary hypertension and right ventricular (RV) hypertrophy. We previously showed that inflammation and regulatory T cells (Tregs) modulate HF progression in mice with preexisting LV failure. The main objective of this study is to determine the role of CD8+ T cells in modulating LV failure and the consequent pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure. Methods: Mice with LV failure produced by transverse aortic constriction (TAC) were randomized to depletion of cytotoxic CD8+ T cells, Tregs, or both using specific blocking antibodies. Cardiac function, lung inflammation, fibrosis, vascular remodeling, and right ventricular remodeling were determined. Results: LV failure caused pulmonary inflammation, fibrosis, vascular remodeling, and RV hypertrophy. Depletion of CD8+ T cells significantly attenuated above changes in mice with preexisting LV failure. LV failure was associated with increased CD4+ and CD8+ T cell activation, and increased ratios of activated T cells to Tregs. Treg depletion exacerbated lung inflammation and HF progression, as well as lung CD4+ and CD8+ T cell infiltration and activation in HF mice. However, CD8+ T cells depletion rescue these mice from exacerbated lung inflammation and RV hypertrophy after Treg depletion. Discussion: Our findings demonstrate an important role of CD8+ T cells in promoting pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure. Depletion of CD8+ T cells also rescued HF mice from the exacerbated HF progression by Treg depletion. [ABSTRACT FROM AUTHOR]

Discoidin, CUB, LCCL domain‐containing 2 (DCBLD2) is a type I transmembrane protein with a similar structure to neuropilin, which acts as a co‐receptor for certain receptor tyrosine kinases (RTKs). The insulin receptor is an RTK and plays a critical role in endothelial cell function and glycolysis. However, how and whether DCBLD2 regulates insulin receptor activity in endothelial cells is poorly understood. Diabetes was induced through treatment of Dcbld2 global‐genome knockout mice and endothelium‐specific knockout mice with streptozotocin. Vascular ultrasound, vascular tension test, and hematoxylin and eosin staining were performed to assess endothelial function and aortic remodeling. Glycolytic rate assays, real‐time PCR and western blotting were used to investigate the effects of DCBLD2 on glycolytic activity and insulin receptor (InsR)/phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway in endothelial cells. Co‐immunoprecipitation was used to assess the effects of DCBLD2 on insulin receptor endocytosis and recycling. Membrane and cytoplasmic proteins were isolated to determine whether DCBLD2 could affect the localization of the insulin receptor. We found that Dcbld2 deletion exacerbated endothelial dysfunction and vascular remodeling in diabetic mice. Both Dcbld2 knockdown and Dcbld2 deletion inhibited glycolysis and the InsR/PI3K/Akt signaling pathway in endothelial cells. Furthermore, Dcbld2 deletion inhibited insulin receptor recycling. Taken together, Dcbld2 deficiency exacerbated diabetic endothelial dysfunction and vascular remodeling by inhibiting the InsR/PI3K/Akt pathway in endothelial cells through the inhibition of Rab11‐dependent insulin receptor recycling. Our data suggest that DCBLD2 is a potential therapeutic target for diabetes and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

(200/200) Purpose: Our aim was to evaluate structural alterations of retinal arterioles due to type 1 diabetes (T1D) and/or diabetic retinopathy (DR) under AOSLO imaging. Methods: Each study eye underwent mydriasis and AOSLO imaging in a single-visit study. The instrument's arrangement of four offset aperture images provided two orthogonal split-detector images and enabled isotropic analysis of the arteriolar boundaries. For each arteriole, we calculated the wall-to-lumen ratio (WLR), mean wall thickness, and luminal and external diameters. Results: In total, we enrolled 5 (20.8%) healthy control eyes and 19 eyes of patients with T1D. The DR distribution was: four (16.7%) no-DR, nine (37.5%%) mild or moderate nonproliferative DR (NPDR), and six (25%) severe NPDR or proliferative DR. Mean wall thickness increased significantly in eyes with T1D compared to healthy controls (p = 0.0006) and in eyes with more advanced DR (p = 0.0004). The WLR was significantly higher in eyes with T1D (p = 0.002) or more severe DR (p = 0.004). There was no significant relationship between T1D status or DR severity and any of the arteriolar diameters. Conclusions: In this preliminary study, there appeared to be increases in the WLR and mean wall thickness in eyes with T1D and more severe DR than in the controls and eyes with no/less severe DR. Future studies may further elucidate the relationship between the retinal arteriolar structure and physiologic alterations in DR. [ABSTRACT FROM AUTHOR]

Classic and non‐classic cardiovascular (CV) risk factors accumulate in chronic kidney disease (CKD), contributing to vascular remodeling and hemodynamic abnormalities. This study aimed to determine hemodynamic phenotypes based on linear regression of blood pressure (BP) parameters in stage G3‐G4 CKD patients at very high CV risk. 24‐h ambulatory BP monitoring (ABPM), carotid‐femoral pulse wave velocity (PWV) and central BP were obtained from 52 patients (aged 60 ± 11 years, BMI 30 ± 6 kg/m2) with stage G3‐G4 CKD (eGFR 44 ± 12 mL/min./1.73 m2). Linear BP regression coefficients were generated to determine hemodynamic phenotypes using ABPM data. Coexisting hypertension was present in 45 (86%) patients, out of whom 33 (73%) had BP controlled. 24‐h mean systolic/diastolic BP was 128 ± 18/75 ± 12 mm Hg. Twenty‐six patients demonstrated the harmonious (H) and 26 patients diastolic dysfunctional (D) hemodynamic phenotypes. eGFR was not significantly different between both phenotypes. Compared to phenotype H, patients with phenotype D were older (57 ± 11 vs. 63 ± 10 years, p = .04), had higher PWV (8.2 [7.3–10.3] vs. 9.7 [8.3–10.9] m/s, p = .02), ambulatory arterial stiffness index (AASI) (0.31 ± 0.1 vs. 0.40 ± 0.1, p = .02), systolic BP (128 [122–130] vs. 137 [130–150] mm Hg, p = .001) and systolic BP variability (BPV) (11.7 ± 2.3 vs. 15.7 ± 3.4 mm Hg, p < .0001). Our findings suggest that one in two patients with stage G3‐G4 CKD demonstrates an unfavorable D hemodynamic phenotype based on a linear regression model, associated with higher PWV, AASI, systolic BP, and systolic BPV. Further studies are required to assess the clinical utility of hemodynamic phenotypes and whether the D phenotype may predict latent circulatory disorders and outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. METHODS: Using skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. RESULTS: Sirt3skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle--specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet--induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms (IAs) may afflict up to 5% of the general population, or up to 15 million individuals in the US. The two forms of IAs that can be recognized by their shape are saccular and nonsaccular IAs, with uncommon aneurysm types, fusiform and dissecting aneurysms, comprising 13% of nonsaccular IAs. Conceivably, among the various risk factors for IA development, vessel wall inflammation represents a major cause. Accordingly, IAs may not necessarily be the result of passive widening of vessel wall structures, but may also be the result of inflammation and tissue degeneration. Thus, flow‐induced vascular remodeling during IA pathogenesis may reflect immune cell infiltration and consequent release of proinflammatory cytokine, chemokine, and matrix metalloproteinase that contribute to vessel wall degeneration and weakening. Thus, infiltrating neutrophils, macrophages, T‐lymphocytes and complement factors, and the resulting immune microenvironment may be pertinent in IA pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear. Methods: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro. Results: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice. Conclusions: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases. [ABSTRACT FROM AUTHOR]

Background: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive. Methods and results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats. Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH. [ABSTRACT FROM AUTHOR]

Caveolae are intracellular vesicles with diameters ranging from 50 to 100 nm. The role of caveolins in mediating oxidative stress, autophagy, apoptosis, fibrosis, and vascular remodeling has attracted increasing attention in cardiovascular therapy. Several studies have suggested that caveolin could be a therapeutic target for the treatment of cardiac and/or vascular injury via several pathophysiological mechanisms. Despite substantial advances in our understanding of the basic biology of vesicles over the past decade, the relevance and specific role of these mechanisms in cardiovascular homeostasis remains ambiguous. Here, we review the macroscopic role of caveolins in protecting cardiac function and, at the microscopic level, examine possible cardioprotective caveolar mechanisms, including their antioxidative stress, antiapoptosis, autophagy‐regulatory, antifibrosis, and angiogenesis‐promoting properties. We believe that the role of caveolins in cardiac functioning has not been fully elucidated and is an important line of future research with several cardioprotective implications. [ABSTRACT FROM AUTHOR]

Atherosclerosis, marked by plaque accumulation within arteries, results from lipid dysregulation, inflammation, and vascular remodeling. Plaque composition, including lipid-rich cores and fibrous caps, determines stability and vulnerability. Photodynamic therapy (PDT) has emerged as a promising treatment, leveraging photosensitizers to induce localized cytotoxicity upon light activation. PDT targets plaque components selectively, reducing burden and inflammation. Challenges remain in optimizing PDT parameters and translating preclinical success to clinical efficacy. Nonetheless, PDT offers a minimally invasive strategy for atherosclerosis management, promising personalized interventions for cardiovascular health. The objective of the current study was to present the findings from quantitative non-contrast MRI of atherosclerosis post-PDT by assessing relaxation times. The study aimed to utilize and optimize a 1.5T MRI system. Clinical scanners were used for MRI examinations. The research involved analyzing T1 and T2 relaxation times. Following treatment of the samples with Rose Bengal and exposure to pure oxygen, PDT irradiation was administered. The results indicated that the therapy impacted the crus, evidenced by a significant decrease in relaxation times in the MRI data. [ABSTRACT FROM AUTHOR]

As an essential trace element, copper has major effects on cell metabolism. Therefore, interfering with the balance of copper metabolism in such a way that leads to copper deficiency or excess causes disease. It has been reported that copper metabolic imbalance, or cuproptosis, affects the development of cardiovascular diseases by mediating cellular oxidative stress and vascular remodeling and by interfering with mitochondrial functions. Importantly, copper chelators, copper ion carriers, small molecule inhibitors of copper chaperones, and dietary copper can alleviate cardiovascular diseases caused by copper metabolic imbalance or cuproptosis. In this review, we comprehensively considered the molecular mechanisms of copper metabolic homeostasis and cuproptosis, as well as their significance and therapeutic advances in cardiovascular diseases, aiming to provide insights on therapeutically targeting copper metabolic homeostasis and cupro-ptosis as a novel strategy for managing cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is relatively common, affecting up to 50% of patients with idiopathic pulmonary fibrosis (IPF). It occurs more frequently in advanced fibrotic ILD, although it may also complicate milder disease and carries significant clinical implications in terms of morbidity and mortality. Key pathological processes driving ILD-PH include hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. While current understanding of the complex cell signalling pathways and molecular mechanisms underlying ILD-PH remains incomplete, there is evidence for an interplay between the disease pathogenesis of fibrotic ILD and PH, with interest in the role of the pulmonary endothelium in driving pulmonary fibrogenesis more recently. This review examines key clinical trials in ILD-PH therapeutics, including recent research showing promise for the treatment of both ILD-PH and the underlying pulmonary fibrotic process, further supporting the hypothesis of interrelated pathogenesis. Other important management considerations are discussed, including the value of accurate phenotyping in ILD-PH and the success of the "pulmonary vascular" phenotype. This article highlights the close and interconnected nature of fibrotic ILD and PH disease pathogenesis, a perspective likely to improve our understanding and therapeutic approach to this complex condition in the future. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is a group of diseases characterized by elevated pulmonary artery pressure and pulmonary vascular resistance with significant morbidity and mortality. The most prevalent type is pulmonary hypertension secondary to left heart disease (PH-LHD). The available experimental models of PH-LHD use partial pulmonary clamping by technically nontrivial open-chest surgery with lengthy recovery. We present a simple model in which the reduction of the cross-sectional area of the ascending aorta is achieved not by external clamping but by partial intravascular obstruction without opening the chest. In anesthetized rats, a blind polyethylene tubing was advanced from the right carotid artery to just above the aortic valve. The procedure is quick and easy to learn. Three weeks after the procedure, left heart pressure overload was confirmed by measuring left ventricular end-diastolic pressure by puncture (1.3 ± 0.2 vs. 0.4 ± 0.3 mmHg in controls, mean ± SD, P < 0.0001). The presence of pulmonary hypertension was documented by measuring pulmonary artery pressure by catheterization (22.3 ± 2.3 vs. 16.9 ± 2.7 mmHg, P = 0.0282) and by detecting right ventricular hypertrophy and increased muscularization of peripheral pulmonary vessels. Contributions of a precapillary vascular segment and vasoconstriction to the increased pulmonary vascular resistance were demonstrated, respectively, by arterial occlusion technique and by normalization of resistance by a vasodilator, sodium nitroprusside, in isolated lungs. These changes were comparable, but not additive, to those induced by an established pulmonary hypertension model, chronic hypoxic exposure. Intravascular partial aortic obstruction offers an easy model of pulmonary hypertension induced by left heart disease that has a vasoconstrictor and precapillary component. NEW & NOTEWORTHY: We present a new, simple model of a clinically important type of pulmonary hypertension, that induced by left heart failure. Left ventricular pressure overload is induced in rats by inserting a blinded cannula into the ascending aorta via carotid artery access. This partial intravascular aortic obstruction, which does not require opening of the chest and prolonged recovery, causes pulmonary hypertension, which has a precapillary and vasoconstrictor as well as a vascular remodeling component. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) are the primary physiological inhibitors of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but their roles in PAH are unsettled. Here, we report that: 1) PAI-1, but not PAI-2, is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared with controls; 2) PAI-1−/− mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and 3) pharmacological inhibition of uPA in human PAH PASMCs suppresses proproliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation, and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that downregulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent upregulation of mTOR and transforming growth factor-β (TGF-β) signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH. NEW & NOTEWORTHY: This study identifies a novel role for the deficiency of plasminogen activator inhibitor (PAI)-1 and resultant unrestricted uPA activity in PASMC remodeling and PH in vitro and in vivo, provides novel mechanistic link from PAI-1 loss through uPA-induced Akt/mTOR and TGFβ-Smad3 upregulation to pulmonary vascular remodeling in PH, and suggests that inhibition of uPA to rebalance the uPA-PAI-1 tandem might provide a novel approach to complement current therapies used to mitigate this pulmonary vascular disease. [ABSTRACT FROM AUTHOR]

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488–504. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB1Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB1Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB1R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM–1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB1R gene. However, with the defect of the CB1R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB1R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB1R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB1Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB1R gene significantly attenuates vascular damage in hypercholesterolemic mice. [ABSTRACT FROM AUTHOR]

The number of patients with end-stage renal disease (ESRD) requiring hemodialysis is increasing worldwide. Although arteriovenous fistula (AVF) is the best and most important vascular access (VA) for hemodialysis, its primary maturation failure rate is as high as 60%, which seriously endangers the prognosis of hemodialysis patients. After AVF establishment, the venous outflow tract undergoes hemodynamic changes, which are translated into intracellular signaling pathway cascades, resulting in an outward and inward remodeling of the vessel wall. Outward remodeling refers to the thickening of the vessel wall and the dilation of the lumen to accommodate the high blood flow in the AVF, while inward remodeling is mainly characterized by intimal hyperplasia. More and more studies have shown that the two types of remodeling are closely related in the occurrence and development of, and jointly determining the final fate of, AVF. Therefore, it is essential to investigate the underlying mechanisms involved in outward and inward remodeling for identifying the key targets in alleviating AVF dysfunction. In this review, we summarize the current clinical diagnosis, monitoring, and treatment techniques for AVF dysfunction and discuss the possible pathological mechanisms related to improper outward and inward remodeling in AVF dysfunction, as well as summarize the similarities and differences between the two remodeling types in molecular mechanisms. Finally, the representative therapeutic targets of potential clinical values are summarized. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. Methods: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. Results: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. Conclusion: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH. [ABSTRACT FROM AUTHOR]

Background and objectives: Endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) play a pivotal role in the pathophysiology and vascular remodeling of chronic thromboembolic pulmonary hypertension (CTEPH) which is an under-diagnosed complication of acute pulmonary embolism (PE). Currently, pulmonary endarterectomy (PEA) is still the treatment of choice for selected patients suffering from CTEPH. The aim of this study was to evaluate the preoperative and postoperative circulating levels of ET-1 and TGF-β in subjects affected by CTEPH undergoing successful surgical treatment by PEA. Methods: The data from patients diagnosed with CTEPH who underwent PEA at the Foundation IRCCS Policlinico San Matteo Hospital (Pavia, Italy) were prospectively recorded in the Institutional database. Circulating ET-1 and TGF-β levels were assessed by an ELISA commercial kit before PEA, at 3 months and 1 year after PEA. The demographic data, preoperatory mean pulmonary arterial pressure (mPAP), cardiac output (CO), and pulmonary vascular resistance (PVR) were also recorded. Univariate and multivariate analyses were performed. Results: The analysis included 340 patients with complete ET-1 measurements and 206 patients with complete TGF-β measurements. ET-1 significantly decreased both at 3 months (p < 0.001) and at 1 year (p = 0.009) after PEA. On the other hand, preoperatory TGF-β levels did not significantly change after PEA. Furthermore, ET-1, but not TGF-β, was a good predictor for increased mPAP in multivariate analyses (p < 0.05). Conclusions: ET-1 but not TGF β was significantly modulated by PEA in subjects affected by CTEPH up to 1 year after surgery. The mechanisms leading to prolonged elevated circulating TGF-β levels and their clinical significance have to be further elucidated. [ABSTRACT FROM AUTHOR]

We previously reported pulmonary arterial remodelling and active endothelial-to-mesenchymal transition (EndMT) in smokers and patients with early chronic obstructive pulmonary disease (COPD). In the present study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-β1 (P<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (P<0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared with NC. Total β-catenin expression was significantly higher in smoking groups across arterial sizes (P<0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total β-catenin was positively correlated with total S100A4 in small and medium arteries (r = 0.35, 0.50; P=0.02, 0.01, respectively), with Vimentin in medium arteries (r = 0.42, P=0.07), and with arterial thickness of medium and large arteries (r = 0.34, 0.41, P=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway [ABSTRACT FROM AUTHOR]

Hypoxia-induced pulmonary artery hypertension (HPH) is a complication of chronic hypoxic lung disease and the third most common type of pulmonary artery hypertension (PAH). Epigenetic mechanisms play essential roles in the pathogenesis of HPH. N6-methyladenosine (m6A) is an important modified RNA nucleotide involved in a variety of biological processes and an important regulator of epigenetic processes. To date, the precise role of m6A and regulatory molecules in HPH remains unclear. HPH model and pulmonary artery smooth muscle cells (PASMCs) were constructed from which m6A changes were observed and screened for AlkB homolog 5 (Alkbh5). Alkbh5 knock-in (KI) and knock-out (KO) mice were constructed to observe the effects on m6A and evaluate right ventricular systolic pressure (RVSP), left ventricular and septal weight [RV/(LV + S)], and pulmonary vascular remodeling in the context of HPH. Additionally, the effects of Alkbh5 knockdown using adenovirus were examined in vitro on m6A, specifically in PASMCs with regard to proliferation, migration and cytochrome P450 1A1 (Cyp1a1) mRNA stability. In both HPH mice lung tissues and hypoxic PASMCs, a decrease in m6A was observed, accompanied by a significant up-regulation of Alkbh5 expression. Loss of Alkbh5 attenuated the proliferation and migration of hypoxic PASMCs in vitro, with an associated increase in m6A modification. Furthermore, Alkbh5 KO mice exhibited reduced RVSP, RV/(LV + S), and attenuated vascular remodeling in HPH mice. Mechanistically, loss of Alkbh5 inhibited Cyp1a1 mRNA decay and increased its expression through an m6A-dependent post-transcriptional mechanism, which hindered the proliferation and migration of hypoxic PASMCs. The current study highlights the loss of Alkbh5 impedes the proliferation and migration of PASMCs by inhibiting post-transcriptional Cyp1a1 mRNA decay in an m6A-dependent manner. [Display omitted] • The Alkbh5 was upregulated in HPH and resulted in m6A methylation. • Loss of Alkbh5 attenuates the proliferation and migration of PASMCs. • Loss of Alkbh5 attenuates PASMCs remodeling is Cyp1a1 dependent. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary microvasculature leading to elevated precapillary pulmonary hypertension. Pulmonary vascular remodeling, a characteristic of PAH, is driven by dysfunctions in the signaling between the pulmonary smooth muscle and endothelial cells with abnormalities that affect cell proliferation and immune dysregulation. Sotatercept, an activin signaling inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of PAH based on two pivotal clinical trials. Evidence-based clinical trials have provided a framework to guide clinicians treating the disease; however, they are not tailored to the individual patient. Often, recommendations from these data are unclear or too general, due to remaining gaps in knowledge. In this edition of "How I Do It," we provide a case-based discussion of common clinical decisions regarding diagnostic testing, choice of first-line agents, escalation of therapy, potential timing of sotatercept, safety awareness, practical use, potential management changes, and the future use of sotatercept in other pulmonary hypertension cohorts. [ABSTRACT FROM AUTHOR]

Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro‐ and anti‐angiogenic products of the transforming growth factor β/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high‐output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first‐line medical therapy. For non‐responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti‐angiogenetic drugs and those that target aberrant cell signalling pathway are being explored. [ABSTRACT FROM AUTHOR]

Alterations in vascular extracellular matrix (ECM) components, interactions, and mechanical properties influence both the formation and stability of atherosclerotic plaques. This review discusses the contribution of the ECM microenvironment in vascular homeostasis and remodeling in atherosclerosis, highlighting Cartilage oligomeric matrix protein (COMP) and its degrading enzyme ADAMTS7 as examples, and proposes potential avenues for future research aimed at identifying novel therapeutic targets for atherosclerosis based on the ECM microenvironment. [ABSTRACT FROM AUTHOR]

Background: Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this process also leads to programmed death of macrophages. So far, the role of macrophage death in the progression of atherosclerosis remains controversial. Also, the underlying mechanism by which transcriptional regulation and reprogramming triggered by macrophage death pathways lead to changes in vascular inflammation and remodeling are still largely unknown. TRIM25-mediated RIG-I signaling plays a key role in regulation of macrophages fate, however the role of TRIM25 in macrophage death-mediated atherosclerotic progression remains unclear. This study aims to investigate the relationship between TRIM25 and macrophage death in atherosclerosis. Methods: A total of 34 blood samples of patients with coronary stent implantation, including chronic total occlusion (CTO) leisions (n = 14) or with more than 50% stenosis of a coronary artery but without CTO leisions (n = 20), were collected, and the serum level of TRIM25 was detected by ELISA. Apoe−/− mice with or without TRIM25 gene deletion were fed with the high-fat diet (HFD) for 12 weeks and the plaque areas, necrotic core size, aortic fibrosis and inflammation were investigated. TRIM25 wild-type and deficient macrophages were isolated, cultured and stimulated with ox-LDL, RNA-seq, real-time PCR, western blot and FACS experiments were used to screen and validate signaling pathways caused by TRIM25 deletion. Results: Downregulation of TRIM25 was observed in circulating blood of CTO patients and also in HFD-induced mouse aortas. After HFD for 12 weeks, TRIM25−/−ApoeE−/− mice developed smaller atherosclerotic plaques, less inflammation, lower collagen content and aortic fibrosis compared with TRIM25+/+ApoeE−/− mice. By RNA-seq and KEGG enrichment analysis, we revealed that deletion of TRIM25 mainly affected pyroptosis and necroptosis pathways in ox-LDL-induced macrophages, and the expressions of PARP1 and RIPK3, were significantly decreased in TRIM25 deficient macrophages. Overexpression of TRIM25 promoted M1 polarization and necroptosis of macrophages, while inhibition of PARP1 reversed this process. Further, we observed that XRCC1, a repairer of DNA damage, was significantly upregulated in TRIM25 deficient macrophages, inhibiting PARP1 activity and PARP1-mediated pro-inflammatory change, M1 polarization and necroptosis of macrophages. By contrast, TRIM25 overexpression mediated ubiquitination of XRCC1, and the inhibition of XRCC1 released PARP1, and activated macrophage M1 polarization and necroptosis, which accelerated aortic inflammation and atherosclerotic plaque progression. Conclusions: Our study has uncovered a crucial role of the TRIM25-XRCC1Ub-PARP1-RIPK3 axis in regulating macrophage death during atherosclerosis, and we highlight the potential therapeutic significance of macrophage reprogramming regulation in preventing the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is defined as an impairment in the vasodilatory, anti-thrombotic, and anti-inflammatory properties of the cells that make up the lining of blood vessels. ED is considered a key step in the development of atherosclerotic cardiovascular disease. The association between ED and systemic inflammatory diseases is well established. However, the prevalence and clinical significance of ED in psoriatic arthritis (PsA) have been investigated to a lesser extent. This review aims to explore the link between ED and PsA, including ED in macro- and microcirculation, as well as risk factors for its occurrence in PsA and its relationship with atherosclerosis in PsA. Furthermore, the ED in PsA was compared with that of rheumatoid arthritis (RA). Regarding ED in the microcirculation, the coronary flow reserve was found to be significantly reduced in individuals with PsA. The relationship between PsA and macrovascular ED is more pronounced, along with more advanced atherosclerosis detected in patients with PsA. These results are consistent with those obtained in RA studies. On the other hand, arterial stiffness and signs of vascular remodeling were found more frequently in RA than in PsA, with the potential role of efficient anti-TNF treatment in patients with PsA and psoriasis explaining this finding. The impact of ED on cardiovascular diseases and the burden of this risk caused independently by PsA have not yet been precisely established, however, this group of patients requires special attention with regard to cardiovascular events. [ABSTRACT FROM AUTHOR]

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo , a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls. CSF levels of VEGF and ET-1 positively correlated with MMP-9 but negatively with MMP-2, suggesting a complex vascular remodeling process occurring in AD. Only MMP-2 levels were significantly associated with CSF AD biomarkers. Conversely, higher MMP-2 (β = 0.411, p < 0.001), ET-1 levels (β = 0.344, p < 0.001) and VEGF (β = 0.221, p = 0.022), were associated with higher BBB permeability. Astrocytic-derived vascular remodeling factors are altered in AD, disclosing the failure of important protective mechanisms which proceed independently alongside AD pathology. • Astrocytic-derived vascular remodeling factors can be measured in AD patients' CSF. • Astrocytic-derived VEGF, MMP-2 and MMP-9 CSF levels are reduced in AD patients. • MMP-2 CSF levels associate with AD core biomarkers. • MMP-2, ET-1 and VEGF CSF levels contribute to BBB regulation in AD. [ABSTRACT FROM AUTHOR]