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Objectives: This study was performed to assess postoperative aortic remodelling (AR) after total arch replacement for acute type A aortic dissection (AAD) with a frozen elephant trunk (FET) or conventional elephant trunk (cET). Furthermore, the shape of the residual true lumen was analysed based on elliptical Fourier analysis and evaluated as a predictor of AR., Methods: This study involved patients who underwent total arch replacement with a cET or FET for AAD from December 2006 to January 2023 at five institutions. AR was assessed at the levels of the 4th thoracic vertebra (Th4), Th7, Th10, and above the coeliac trunk. The shape of the residual true lumen at all four levels was analysed based on elliptical Fourier analysis to calculate shape patterns as principal component (PC) values. Inverse probability of treatment weighting was performed for adjustment between the groups., Results: In total, 180 patients (88 with cET and 92 with FET) were enrolled. The complete AR rate, defined as false lumen remodelling throughout the entire descending thoracic aorta, was significantly higher in the FET than cET group (63.4% vs 32.0%, P = 0.0013). The inverse probability of treatment weighting-adjusted Fine-Gray regression model revealed that the mean PC2 (hazard ratio, 0.22; P < 0.001) and PC3 (hazard ratio, 0.24; P = 0.009) of the four levels were independent predictors of complete AR., Conclusions: In AAD repair, the AR rate was significantly higher with use of the FET than cET. The shape patterns of the residual true lumen can be an important reference for predicting postoperative AR., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca 2+ ] m ) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca 2+ ] m in preeclampsia development remains largely unknown., Methods: To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester-induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca 2+ ] m to improve the outcome for preeclamptic mothers or their infants., Results: Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca 2+ ] m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na + /Ca 2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na + /Ca 2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia-derived VSMCs and the preeclampsia rat model., Conclusions: This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca 2+ ] m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia., Competing Interests: None.

This work probed into the role of latent transforming growth factor beta binding protein 2 (LTBP2) in intracranial aneurysm (IA). The rats underwent IA modeling and then stereotactic injection of short hairpin RNA against LTBP2 (shLTBP2). Hematoxylin-eosin (HE) staining was employed to assess IA model and vascular remodeling. Rat vascular smooth muscle cells (VSMCs) were transfected with shLTBP2, LTBP2 overexpression plasmid and fibroblast growth factor 2 (FGF2) overexpression plasmid. The mRNA and protein expressions of LTBP2, FGF2 and mitochondrial apoptosis-related factors (Caspase-3, Cyt-c, Mcl-1) were tested through qRT-PCR and Western blot. Cell viability, proliferation and apoptosis were examined by cell counting kit-8, EdU assay and flow cytometry. The up-regulated LTBP2 and down-regulated FGF2 were detected in IA rats. LTBP2 knockdown promoted vascular remodeling and Mcl-1 level, and restrained cell apoptosis and expressions of Caspase-3 and Cyt-c in IA model rats. Moreover, LTBP2 knockdown potentiated cell viability, proliferation and FGF2 level, and repressed apoptosis in rat VSMCs, while overexpressed LTBP2 exerted opposite effects. FGF2 overexpression promoted proliferation and Mcl-1 level, and inhibited apoptosis and expressions of Caspase-3 and Cyt-c in rat VSMCs, which also reversed the effects of overexpressed LTBP2 on these aspects. Collectively, LTBP2 down-regulates FGF2 to repress VSMCs proliferation and vascular remodeling in an IA rat model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pathological vascular remodeling of the vessel wall refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease. The vessel wall is composed of two main types of cells, endothelial cells and vascular smooth muscle cells, whose communication is crucial in both the development of the vasculature and the homeostasis of mature vessels. Changes in the dialogue between endothelial cells and vascular smooth muscle cells are associated with various pathological states that triggers remodeling of the vascular wall. For many years, considerable efforts have been made to develop effective diagnoses and treatments for these pathologies by studying their mechanisms in both in vitro and in vivo models. Compared to animal models, in vitro models can provide great opportunities to obtain data in a more homogeneous, economical and massive way, providing an overview of the signaling pathways responsible for these pathologies. The implementation of three-dimensional in vitro co-culture models for the study of other pathologies has been postulated as a potentially applicable methodology, which determines the importance of its application in studies of cardiovascular diseases. In this article we present a method for culturing human endothelial cells and vascular smooth muscle cells, grown under non-adherent conditions, that generate three-dimensional spheroidal structures with greater physiological equivalence to in vivo conditions. This in vitro modeling could be used as a study tool to identify cellular and molecular mechanisms involved in the pathological processes underlying vascular remodeling., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

In recent years, major advances have been made in the understanding of the cellular and molecular mechanisms driving pulmonary vascular remodelling in various forms of pulmonary hypertension, including pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic lung disease and hypoxia, and chronic thromboembolic pulmonary hypertension. However, the survival rates for these different forms of pulmonary hypertension remain unsatisfactory, underscoring the crucial need to more effectively translate innovative scientific knowledge into healthcare interventions. In these proceedings of the 7th World Symposium on Pulmonary Hypertension, we delve into recent developments in the field of pathology and pathophysiology, prioritising them while questioning their relevance to different subsets of pulmonary hypertension. In addition, we explore how the latest omics and other technological advances can help us better and more rapidly understand the myriad basic mechanisms contributing to the initiation and progression of pulmonary vascular remodelling. Finally, we discuss strategies aimed at improving patient care, optimising drug development, and providing essential support to advance research in this field., Competing Interests: Conflict of interest: C. Guignabert reports grants from Acceleron Pharma, MSD, Corteria Pharmaceuticals, Structure Therapeutics (ex-ShouTi) and Gossamer Bio, payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, and patents planned, issued or pending (WO/2024/023139, WO/2018/011376). J. Aman has no potential conflicts of interest to disclose. S. Bonnet reports grants from Morphic Therapeutic, Sunshine Bio and Janssen, consultancy fees from Morphic Therapeutic and Chiesi, and participation on a data safety monitoring board or advisory board with Morphic Therapeutic and Allienaire. P. Dorfmüller reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca. A.J. Olschewski reports grants from Austrian Science Fund (FWF) (10.55776/I6299 and 10.55776/KLI1153), payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, patents pending (PCT/EP2017/055440), and stock (or stock options) with Bayer. S. Pullamsetti reports grants and consultancy fees from Gossamer Bio. M. Rabinovitch reports consultancy fees from Pfizer, Amgen, Merck and Tiakis, payment or honoraria for lectures, presentations, manuscript writing or educational events from NIH, patents planned, issued or pending (FK506: tacrolimus in pulmonary hypertension), participation on a data safety monitoring board or advisory board with Amgen and NIH, is associate editor for JACC BTS, receipt of equipment, materials, drugs, medical writing, gifts or other services from Tiakis (tiprelestat). R.T. Schermuly reports grants from Chiesi and Attgeno, and consultancy fees from Gossamer, Attgeno and Chiesi. M. Humbert reports grants from Gossamer and Merck, consultancy fees from 35 Pharma, Aerovate, AOP Orphan, Chiesi, Ferrer, Gossamer, Janssen, Keros, Liquidia, Merck, Novartis, Respira, Roivant and United Therapeutics, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen and Merck, and participation on a data safety monitoring board or advisory board with 35 Pharma, Aerovate, Janssen, Keros, Merck, Novartis and United Therapeutics. K.R. Stenmark reports grants from NIH/NHLBI and DoD, and a leadership role with PVRI., (Copyright ©The authors 2024.)

Preeclampsia (PE) is a multisystem pregnancy disorder characterized by impaired remodeling of placental spiral arteries, which leads to the release of pro-inflammatory cytokines and anti-angiogenic agents. However, treatment options for PE are limited, with termination of pregnancy being the only curative option. In this work, we investigated the effects of human amniotic epithelial cells (hAECs) in PE rat model. The rats were induced with lipopolysaccharide (LPS) on gestational day 14.5 followed by injection of hAECs and human umbilical cord mesenchymal stem cells 24 h later. The hAECs treatment resulted in a reduction in blood pressure and proteinuria in the PE rat model. Furthermore, hAECs treatment decreased levels of pro-inflammatory cytokines, reduced inflammatory cells aggregation, and alleviated the damage to placental spiral arteries by downregulating the expression of anti-angiogenic factor and upregulating proangiogenic factor. In vitro experiments confirmed that hAECs treatment restored the proliferation, migration, and angiogenesis of LPS-damaged human umbilical vein endothelial cells. Additionally, hAECs treatment had positive effects on fetal weight and neurological development in the PE group, with no negative effects on the physical development or fertility of offspring rats. These results suggested that hAECs transplantation may be a novel adjuvant therapeutic strategy for PE by reducing the inflammatory and enhancing placental spiral artery angiogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vascular remodeling is the main pathological process that causes the damage of the target organ of hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and plays a key role in the pathogenesis of various cardiovascular diseases. This study aimed to investigate the effects of renal denervation (RDN) on hypertensive vascular remodeling and to elucidate the role of PVAT in this process. Male spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat were selected. Aortic vascular remodeling was evaluated using hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Morphological changes in the PVAT were observed through H&E and Oil Red O staining. Dihydroethidium was used to measure oxidative stress levels in PVAT, while western blot analysis was used to determine the expression levels of proteins associated with vascular remodeling. The results showed that the aortic medial thickness, media thickness/lumen diameter, collagen volume fraction, and reactive oxygen species (ROS) level in PVAT were significantly higher in the SHR group than in the WKY group. The indexes mentioned above were lower in the SHR-RDN group than in the SHR group. H&E staining revealed that fat droplets in PVAT in the SHR-RDN group became smaller and browning occurred. Moreover, the protein expression of uncoupling protein-1 (UCP-1) and neuregulin 4 (Nrg4) was significantly increased in the SHR-RDN group. In addition, the expression of adiponectin increased and the expression of leptin decreased in the SHR-RDN group compared to the SHR group. In conclusion, RDN can relieve hypertensive vascular remodeling, which may be associated with PVAT., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

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.

Preeclampsia is a pregnancy-related disorder manifested as hypertensive pregnancy (HTN-Preg) and often fetal growth restriction (FGR), but the mechanisms involved are unclear. We have reported enhanced reactivity of systemic vessels in HTN-Preg rats, but the critical changes in the uterine circulation are less clear. We tested whether HTN-Preg involves localized aberrations in uterine arterial tone, stiffness and remodeling by matrix metalloproteinases (MMPs). Blood pressure (BP) and litter size were recorded in normal pregnant (Preg) rats and Preg rats with reduced uteroplacental perfusion pressure (RUPP). Isolated uterine arteries were placed in a pressure myograph for measuring intrinsic and extrinsic tone and arterial stiffness. Arteries were bathed in normal Krebs solution (2.5 mM Ca 2+ ), Ca 2+ -free (2 mM EGTA) Krebs, treated with sodium nitroprusside (SNP), or endothelium denuded, then pressurized at 10 mmHg steps from 10 to 110 mmHg, and the % change in diameter was analyzed to measure total (active + passive), active Ca 2+ -dependent myogenic, passive, and endothelium-dependent tone, respectively. BP was higher and the litter size and pup weight were reduced in RUPP vs Preg rats. In normal Krebs, increasing intraluminal pressure caused smaller increments in diameter in arteries of RUPP vs Preg rats, suggesting greater total vascular tone. Arterial incubation in Ca 2+ -free Krebs, treatment with SNP or endothelium-removal abolished the differences in vascular tone, and subtraction of each of these components from total vascular tone revealed significant active Ca 2+ -dependent myogenic, passive, and endothelium-dependent tone, respectively, in RUPP vs Preg rats. The total and passive strain-stress curves were shifted leftward in arteries of RUPP vs Preg rats, indicating increased uterine arterial stiffness. Arterial sections showed decreased lumen/total and increased wall/total area, and immunohistochemistry revealed greater MMP-1 and MMP-7 staining particularly in the media, suggesting uterine arterial remodeling by MMPs in RUPP vs Preg rats. The increased uterine arterial active myogenic, passive, and endothelium-dependent tone, arterial stiffness and remodeling by MMPs would further reduce uterine blood flow and exacerbate uteroplacental ischemia, FGR and HTN-Preg., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Chronic, high-altitude hypoxic exposure increases the risk of high-altitude pulmonary hypertension (PH). Emerging evidence shows maternal exercise may improve offspring resistance to disease throughout life. The purpose of this study is to determine if maternal exercise mitigates chronic hypoxic-induced changes in the offspring indicative of high-altitude PH development., Methods: Female adult C57BL/6J mice were randomly allocated to nonexercise or exercise conditions. Exercise consisted of voluntary running wheel exercise for 4 wk during the perinatal period. Three days after birth, the pups remained at low altitude (normoxia) or were exposed to hypobaric hypoxia of 450 mm Hg to simulate ~4500 m of altitude exposure until 8 wk of age. The study consisted of four groups: hypoxia + nonexercise pregnancy, hypoxia + exercise, or the respective normoxia conditions (normoxia + nonexercise or normoxia + exercise). Offspring body size, motor function, right ventricular systolic pressure (RVSP), and cardiopulmonary morphology were assessed after 8 wk in normoxia or hypoxia., Results: Both hypoxic groups had smaller body sizes, reduced motor function, increased hematocrit, RVSP, muscularization in medium-sized pulmonary arteries, as well as right ventricular hypertrophy and contractility compared with the normoxic groups ( P < 0.05)., Conclusions: Chronic hypoxia simulating 4500 m attenuated growth, lowered motor function, and elicited PH development. Voluntary maternal exercise did not significantly decrease RVSP in the offspring, which aligned with a lack of effect to attenuate abnormal body size and cardiopulmonary development due to chronic hypoxia. These findings are preliminary in nature, and more powered studies through larger group sizes are required to generalize the results to the population., (Copyright © 2024 by the American College of Sports Medicine.)

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., (© 2024. The Author(s).)

Objectives: During human pregnancy, placental extravillous trophoblasts replace vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling them into distensible low-resistance vessels to promote placental perfusion. The present study determined whether B-flow/spatiotemporal image correlation (STIC) M-mode ultrasonography provides an in-vivo imaging method able to digitally quantify spiral artery luminal distensibility as a physiological index of spiral artery remodeling during the advancing stages of normal human pregnancy., Methods: A prospective, longitudinal, observational study was conducted to quantify spiral artery distensibility (i.e. vessel luminal diameter at systole minus diameter at diastole) by B-flow/STIC M-mode ultrasonography during the first, second and third trimesters in 290 women exhibiting a normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), growth factors that modulate important events in spiral artery remodeling, were quantified in a subset of the women in the first, second and third trimesters of pregnancy., Results: Median (interquartile range (IQR)) spiral artery distensibility increased progressively between the first (0.17 (0.14-0.21) cm), second (0.23 (0.18-0.28) cm) and third (0.26 (0.21-0.35) cm) trimesters of pregnancy (P < 0.0001 for all). Median (IQR) spiral artery volume flow increased progressively between the first (2.49 (1.38-4.99) mL/cardiac cycle), second (3.86 (2.06-6.91) mL/cardiac cycle) and third (7.79 (3.83-14.98) mL/cardiac cycle) trimesters (P < 0.001 for all). In accordance with the elevation in spiral artery distensibility, the median (IQR) ratio of serum PlGF/sFlt-1 × 10 3 levels increased between the first (7.2 (4.5-10.0)), second (22.7 (18.6-42.2)) and third (56.2 (41.9-92.5)) trimesters (P < 0.001 for all)., Conclusions: The present study shows that B-flow/STIC M-mode ultrasonography provides an in-vivo imaging technology to quantify digitally the structural and physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose of Review: To provide timely and relevant insights into the complex relationship between pulmonary vascular disease (PVD) and chronic lung disease (CLD), focusing on the causative and consequential dynamics between these conditions., Recent Findings: There are shared pathogenic mechanisms between pulmonary arterial hypertension (PAH) and group 3 pulmonary hypertension, including altered expression of mediators and growth factors implicated in both conditions. Factors such as hypoxia, hypoxemia, and hypercapnia also contribute to pulmonary vascular remodelling and endothelial dysfunction. However, the role of hypoxia as the sole driver of pulmonary hypertension in CLD is being reconsidered, particularly in chronic obstructive pulmonary disease (COPD), with evidence suggesting a potential role for cigarette smoke products in initiating pulmonary vascular impairment. On the other hand, interstitial lung disease (ILD) encompasses a group of heterogeneous lung disorders characterized by inflammation and fibrosis of the interstitium, leading to impaired gas exchange and progressive respiratory decline, which could also play a role as a cause of pulmonary hypertension., Summary: Understanding the intricate interplay between the pulmonary vascular compartment and the parenchymal and airway compartments in respiratory disease is crucial for developing effective diagnostic and therapeutic strategies for patients with PVD and CLD, with implications for both clinical practice and research., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

The compound 6:2 chlorinated polyfluorinated ether sulfonate (F53B), an alternative to perfluorooctane sulfonate (PFOS), has been widely utilized in China. Although the connection between the exposure and toxicity of F53B is established, the role and mechanisms of the compound in promoting vascular remodeling are yet to be elucidated. Thus, the present study investigated the impact of F53B on the function of vascular smooth muscle cells (VSMCs) and vascular remodeling. The data exhibited that F53B stimulates vascular morphological alterations in vivo, and exposure to the compound caused excessive VSMCs ferroptosis and phenotype switching, as determined using phenotype and molecular assays. Moreover, Fer-1 reversed F-53B-induced VSMC dysfunction and vascular remodeling. Furthermore, F53B activated the ferroptosis-related pathway, encompassing ATR expression and LOC101929922/miR-542-3p/ACSL4 pathway. Thus, the current results elaborated on the multifaceted toxicities of F53B that induce vascular remodeling, thereby necessitating the assessment of vasotoxicity risks associated with the compound., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cellular senescence, a permanent halt in cell division due to stress, spurs functional and structural changes, contributing to vascular aging characterized by endothelial dysfunction and vascular remodeling. This process raises the risk of ischemic stroke (IS) in older individuals, with its mechanisms still not completely understood despite ongoing research efforts. In this review, we have analyzed the impact of vascular aging on increasing susceptibility and exacerbating the pathology of IS. We have emphasized the detrimental effects of endothelial dysfunction and vascular remodeling influenced by oxidative stress and inflammatory response on vascular aging and IS. Our goal is to aid the understanding of vascular aging and IS pathogenesis, particularly benefiting older adults with high risk of IS.

Purpose of Review: This review investigates the relationship between myocardial bridges (MBs), intimal thickening in coronary arteries, and Atherosclerotic cardiovascular disease. It focuses on the role of mechanical forces, such as circumferential strain, in arterial wall remodeling and aims to clarify how MBs affect coronary artery pathology., Review Findings: MBs have been identified as influential in modulating coronary artery intimal thickness, demonstrating a protective effect against thickening within the MB segment and an increase in thickness proximal to the MB. This is attributed to changes in mechanical stress and hemodynamics. Research involving arterial hypertension models and vein graft disease has underscored the importance of circumferential strain in vascular remodeling and intimal hyperplasia. Understanding the complex dynamics between MBs, mechanical strain, and vascular remodeling is crucial for advancing our knowledge of coronary artery disease mechanisms. This could lead to improved management strategies for cardiovascular diseases, highlighting the need for further research into MB-related vascular changes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mechanical forces related to blood pressure and flow patterns play a crucial role in vascular homeostasis. Perturbations in vascular stresses and strain resulting from changes in hemodynamic may occur in pathological conditions, leading to vascular dysfunction as well as in vascular prosthesis, arteriovenous shunt for hemodialysis and in mechanical circulation support. Turbulent-like blood flows can induce high-frequency vibrations of the vessel wall, and this stimulus has recently gained attention as potential contributors to vascular pathologies, such as development of intimal hyperplasia in arteriovenous fistula for hemodialysis. However, the biological response of vascular cells to this stimulus remains incompletely understood. This review provides an analysis of the existing literature concerning the impact of high-frequency stimuli on vascular cell morphology, function, and gene expression. Morphological and functional investigations reveal that vascular cells stimulated at frequencies higher than the normal heart rate exhibit alterations in cell shape, alignment, and proliferation, potentially leading to vessel remodeling. Furthermore, vibrations modulate endothelial and smooth muscle cells gene expression, affecting pathways related to inflammation, oxidative stress, and muscle hypertrophy. Understanding the effects of high-frequency vibrations on vascular cells is essential for unraveling the mechanisms underlying vascular diseases and identifying potential therapeutic targets. Nevertheless, there are still gaps in our understanding of the molecular pathways governing these cellular responses. Further research is necessary to elucidate these mechanisms and their therapeutic implications for vascular diseases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-β1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFβ pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFβ1 and p-Smad2/3. Furthermore, TGFβ1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFβ1/Smad2/3 pathway via Nbl1., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: As a significant bridge between perforasomes, choke vessels are the key structure of blood supply expansion, also a prerequisite for preventing distal ischemic necrosis of the multiterritory perforator flap, where the remodeling of choke vessels after flap elevation plays an essential role. This systematic review highlights the underlying mechanisms and clinical ways to promote remodeling of choke vessels, as well as experimental observation approaches to further guide researchers., Methods: A systematic review was conducted from 1975 to 2023 through PubMed, EMBASE, Web of Science, and Cochrane database with the key words "choke vessels" and "perforator flap" to investigate the mechanisms and ways to promote remodeling of choke vessels as well as observation approaches. The inclusion criteria and exclusion criteria were set to screen the literature., Results: A total of 94 literatures were obtained through database retrieval. After removing the duplicate literature, reading the title and abstract, and reviewing the full text finally, 33 articles were included in the final study., Conclusions: The underlying remodeling of choke vessels may be related to fluid shear stress, hypoxia, and inflammation. The clinical ways to promote remodeling of choke vessels include surgical delay, arterial supercharge, venous superdrainage, drugs, and stem cells. Various experimental methods of observing microvascular morphology allow for a comprehensive research of choke vessels., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response., Methods: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1 -/- mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion., Results: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1 -/- mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH., Conclusions: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH., Competing Interests: None.

Background: The N6-methyladenosine (m 6 A) modification of RNA and its regulators have important roles in the pathogenesis of pulmonary hypertension (PH). Ythdf2 (YTH N6-methyladenosine RNA binding protein 2) is best known for its role in degrading m 6 A-modified mRNAs such as Hmox1 mRNA, which leads to alternative activation of macrophages in PH. Recent studies have also linked Ythdf2 to the proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its specific roles in PASMCs and downstream targets during the development of PH remain unclear., Methods: The expression and biological function of Ythdf2 in PASMCs were investigated in human and experimental models of PH. Smooth muscle cell-specific Ythdf2 -deficient mice were used to assess the roles of Ythdf2 in PASMCs in vivo. Proteomic analysis, m 6 A sequencing, and RNA immunoprecipitation analysis were used to screen for potential downstream targets., Results: Ythdf2 was significantly upregulated in human and rodent PH-PASMCs, and smooth muscle cell-specific Ythdf2 deficiency ameliorated PASMC proliferation, right ventricular hypertrophy, pulmonary vascular remodeling, and PH development. Higher expression of Ythdf2 promoted PASMC proliferation and PH by paradoxically stabilizing Myadm mRNA in an m 6 A-dependent manner. Loss of Ythdf2 decreased the expression of Myadm in PASMCs and pulmonary arteries, both in vitro and in vivo. Additionally, silencing Myadm inhibited the Ythdf2 -dependent hyperproliferation of PASMCs by upregulating the cell cycle kinase inhibitor p21., Conclusions: We have identified a novel mechanism where the increased expression of Ythdf2 stimulates PH-PASMC proliferation through an m 6 A/Myadm/p21 pathway. Strategies targeting Ythdf2 in PASMCs might be useful additions to the therapeutic approach to PH., Competing Interests: None.

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging., (© 2024. The Author(s).)

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling., Methods: Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG's potential as an early preeclampsia predictor using clinical plasma samples., Results: TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors., Conclusions: These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia., Competing Interests: Disclosures None.

Background: In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs., Methods: We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors., Results: We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = -0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH., Conclusions: End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1-2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The mammalian placenta's interface with the parent is a richly vascularized tissue whose development relies upon communication between many different cell types within the uterine microenvironment. The uterine blood vessels of the interface are reshaped during pregnancy into wide-bore, flaccid vessels that convey parental blood to the exchange region of the placenta. Invasive trophoblast as well as parental uterine macrophages and Natural Killer cells are involved in the stepwise remodeling of these vessels and their respective contributions to this crucial process are still being delineated. However, the earliest steps in arteriole remodeling are understudied as they are difficult to study in humans, and other species lack the deep trophoblast invasion that is so prominent a feature of placentation in humans. Here, we further characterize the rat, with deep hemochorial placentation akin to humans, as a model system in which to tease apart the earliest, relatively understudied events in spiral arteriole remodeling. We show that the rat uterine-placental interface increases in size and vascularity rapidly, before trophoblast invasion. The remodeling stages in the arterioles of the rat uterine-placental interface follow a sequence of anatomical changes similar to those in humans, and there are changes to the arterioles' muscular tunica media prior to the marked influx of immune cells. The rat is a tractable model in which to better understand the cell/cell interactions occurring in vivo in an intact tissue microenvironment over time., (© 2024 Anatomical Society.)

Recent evidence suggests that glia maturation factor β (GMFβ) is important in the pathogenesis of pulmonary arterial hpertension (PAH), but the underlying mechanism is unknown. To clarify whether GMFβ can be involved in pulmonary vascular remodeling and to explore the role of the IL-6-STAT3 pathway in this process, the expression of GMFβ in PAH rats is examined and the expression of downstream molecules including periostin (POSTN) and interleukin-6 (IL-6) is measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The location and expression of POSTN is also tested in PAH rats using immunofluorescence. It is proved that GMFβ is upregulated in the lungs of PAH rats. Knockout GMFβ alleviated the MCT-PAH by reducing right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and pulmonary vascular remodeling. Moreover, the inflammation of the pulmonary vasculature is ameliorated in PAH rats with GMFβ absent. In addition, the IL-6-STAT3 signaling pathway is activated in PAH; knockout GMFβ reduced POSTN and IL-6 production by inhibiting the IL-6-STAT3 signaling pathway. Taken together, these findings suggest that knockout GMFβ ameliorates PAH in rats by inhibiting the IL-6-STAT3 signaling pathway., (© 2024 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

Rationale: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a posttranslational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) caused by excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis. Objectives: To characterize the role of hypusine signaling in PAH. Methods: Molecular, genetic, and pharmacological approaches were used both in vitro and in vivo to investigate the role of hypusine signaling in pulmonary vascular remodeling. Measurements and Main Results: Hypusine forming enzymes-deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH)-and hypusinated eukaryotic translation factor 5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro , inhibition of DHPS using N 1 -guanyl-1,7-diaminoheptane or shRNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo , inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice, and its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. With mass spectrometry, hypusine signaling is shown to promote the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation. Conclusions: These findings support inhibiting hypusine signaling as a potential treatment for PAH.

Background: Mitogen-activated protein kinase (MAPK)signaling-mediated smoking-associated pulmonary vascular remodeling (PVR) plays an important role in the pathogenesis of group 3 pulmonary hypertension (PH). And G protein pathway suppressor 2 (GPS2) could suppress G-protein signaling such as Ras and MAPK, but its role in cigarette smoking -induced PVR (CS-PVR) is unclear., Methods: An in vivo model of smoke-exposed rats was constructed to assess the role of GPS2 in smoking-induced PH and PVR. In vitro, the effects of GPS2 overexpression and silencing on the function of human pulmonary arterial smooth cells (HPASMCs) and the underlying mechanisms were explored., Results: GPS2 expression was downregulated in rat pulmonary arteries (PAs) and HPASMCs after CS exposure. More importantly, CS-exposed rats with GPS2 overexpression had lower right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and wall thickness (WT%) than those without. And enhanced proliferation and migration of HPASMCs induced by cigarette smoking extract (CSE) can be evidently inhibited by overexpressed GPS2. Besides, GPS2siRNA significantly enhanced the proliferation, and migration of HPASMCs as well as activated Ras and Raf/ERK signaling, while these effects were inhibited by zoledronic acid (ZOL). In addition, GPS2 promoter methylation level in rat PAs and HPASMCs was increased after CS exposure, and 5-aza-2-deoxycytidine (5-aza) inhibited CSE-induced GPS2 hypermethylation and downregulation in vitro., Conclusions: GPS2 overexpression could improve the CS-PVR, suggesting that GPS2 might serve as a novel therapeutic target for PH-COPD in the future., (© 2024. The Author(s).)

Stromal derived factor 1 (SDF1) has been shown to be involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the detailed molecular mechanisms remain unclear. To address this, we utilized primary cultured rat pulmonary artery smooth muscle cells (PASMCs) and monocrotaline (MCT)-induced PAH rat models to investigate the mechanisms of SDF1 driving PASMCs proliferation and pulmonary arterial remodeling. SDF1 increased runt-related transcription factor 2 (Runx2) acetylation by Calmodulin (CaM)-dependent protein kinase II (CaMKII)-dependent HDAC4 cytoplasmic translocation, elevation of Runx2 acetylation conferred its resistance to proteasome-mediated degradation. The accumulation of Runx2 further upregulated osteopontin (OPN) expression, finally leading to PASMCs proliferation. Blocking SDF1, suppression of CaMKII, inhibition the nuclear export of HDAC4 or silencing Runx2 attenuated pulmonary arterial remodeling and prevented PAH development in MCT-induced PAH rat models. Our study provides novel sights for SDF1 induction of PASMCs proliferation and suggests that targeting SDF1/CaMKII/HDAC4/Runx2 axis has potential value in the management of PAH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The Dissected Aorta Repair Through Stent (DARTS) Implantation trial demonstrated positive proximal aortic remodelling following aortic dissection repair with the AMDS hybrid prosthesis. In this study, we look to identify predictors of aortic remodelling following aortic dissection repair with AMDS including whether communications between branch vessels and the false lumen (FL) predict aortic growth., Methods: The DARTS implantation trial included patients who underwent acute DeBakey type I aortic dissection (ATAD I) repair with the AMDS from March 2017 to January 2019. Anatomic measurements were collected from original computerized tomography scans. Measurements were taken at zones 2, 3, 6 and 9. Patients were grouped based on the number of FL communications with the supra-aortic branch vessels or visceral branch vessels., Results: Forty-seven patients were included in the original DARTS implantation trial. Patients with FL communications with the supra-aortic branch vessels tended to have significant growth at zone 3 (P = 0.02-0.0018), while greater numbers of visceral FL communications tended to predict aortic growth at zones 3 (P = 0.003), 6 (P = 0.017-0.0087) and 9 (P = 0.0016-0.0003)., Conclusions: Aortic remodelling following ATAD I repair using the AMDS may be predicted by local FL communications with branch vessels. Patients undergoing ATAD I repair were more likely to experience significant aortic growth in zone 3 with more head vessel communications and in zones 3, 6 and 9 with more visceral FL communications. Predictors of aortic remodelling may help to guide initial surgical management for aortic dissection patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

The healthy adult aorta is a remarkably resilient structure, able to resist relentless cardiac-induced and hemodynamic loads under normal conditions. Fundamental to such mechanical homeostasis is the mechano-sensitive cell signaling that controls gene products and thus the structural integrity of the wall. Mouse models have shown that smooth muscle cell-specific disruption of transforming growth factor-beta (TGFβ) signaling during postnatal development compromises this resiliency, rendering the aortic wall susceptible to aneurysm and dissection under normal mechanical loading. By contrast, disruption of such signaling in the adult aorta appears to introduce a vulnerability that remains hidden under normal loading, but manifests under increased loading as experienced during hypertension. We present a multiscale (transcript to tissue) computational model to examine possible reasons for compromised mechanical homeostasis in the adult aorta following reduced TGFβ signaling in smooth muscle cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Interactions between extracellular matrix (ECM) proteins and β1 integrins play an essential role maintaining vascular integrity in the brain, particularly under vascular remodeling conditions. As blood vessels in the spinal cord are reported to have distinct properties from those in the brain, here we examined the impact of β1 integrin inhibition on spinal cord vascular integrity, both under normoxic conditions, when blood vessels are stable, and during exposure to chronic mild hypoxia (CMH), when extensive vascular remodeling occurs. We found that a function-blocking β1 integrin antibody triggered a small degree of vascular disruption in the spinal cord under normoxic conditions, but under hypoxic conditions, it greatly enhanced (20-fold) vascular disruption, preferentially in spinal cord white matter (WM). This resulted in elevated microglial activation as well as marked loss of myelin integrity and reduced density of oligodendroglial cells. To understand why vascular breakdown is localized to WM, we compared expression levels of major BBB components of WM and grey matter (GM) blood vessels, but this revealed no obvious differences. Interestingly however, hypoxyprobe staining demonstrated that the most severe levels of spinal cord hypoxia induced by CMH occurred in the WM. Analysis of brain tissue revealed a similar preferential vulnerability of WM tracts to show vascular disruption under these conditions. Taken together, these findings demonstrate an essential role for β1 integrins in maintaining vascular integrity in the spinal cord, and unexpectedly, reveal a novel and fundamental difference between WM and GM blood vessels in their dependence on β1 integrin function during hypoxic exposure. Our data support the concept that the preferential WM vulnerability described may be less a result of intrinsic differences in vascular barrier properties between WM and GM, and more a consequence of differences in vascular density and architecture., (© 2024. The Author(s).)

The proliferation, migration and phenotypic transformation of vascular smooth muscle cells contribute to vascular remodeling and hypertension. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been shown to have anti-inflammatory effects and can protect against different cardiovascular diseases. However, the role and mechanism of RvD1 in hypertension are not clear. The current study investigated the role of RvD1 in Ang II-induced hypertensive mice and Ang II-stimulated rat vascular smooth muscle cells. The results showed that RvD1 treatment significantly attenuated hypertension and vascular remodeling, as indicated by decreases in blood pressure, aortic media thickness and collagen deposition. In addition, RvD1 inhibited the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in vivo and in vitro . Notably, the protective effects of RvD1 were mediated by the Ras homolog gene family member A (RhoA)/mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, our findings demonstrated the potential benefits of RvD1 as a promising therapeutic agent in the treatment of vascular remodeling and hypertension., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Coronary artery disease (CAD) is the most prevalent cardiovascular disease worldwide, resulting in myocardial infarction (MI) and even sudden death. Following percutaneous coronary intervention (PCI), restenosis caused by vascular remodeling is always formed at the stent implantation site. Here, we show that Ginkgolide B (GB), a naturally occurring terpene lactone, effectively suppresses vascular remodeling and subsequent restenosis in wild-type mice following left carotid artery (LCA) injury. Additional experiments reveal that GB exerts a protective effect on vascular remodeling and further restenosis through modulation of the Tgf β 1/Smad signaling pathway in vivo and in human vascular smooth muscle cells (HVSMAs) but not in human umbilical vein endothelial cells (HUVECs) in vitro . Moreover, the beneficial effect of GB is abolished after incubated with pirfenidone (PFD, a drug for idiopathic pulmonary fibrosis, IPF), which can inhibit Tgf β 1. In Tgf β 1 -/- mice, treatment with pirfenidone capsules and Yinxingneizhi Zhusheye (including Ginkgolide B) fails to improve vascular remodeling and restenosis. In conclusion, our data identify that GB could be a potential novel therapeutic agent to block vessel injury-associated vascular remodeling and further restenosis and show significant repression of Tgf β 1/Smad signaling pathway., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Quan Wang et al.)

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure., Methods: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcs ΔVSMC ) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment., Results: In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcs fl/fl ) and DNA-PKcs ΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcs ΔVSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1 S616 , subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration., Conclusion: Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1 S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension., Competing Interests: Declaration of competing interest None of the authors declare any potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Mechanical stimuli from the extracellular matrix (ECM) modulate vascular differentiation, morphogenesis and dysfunction of the vasculature. With innovation in measurements, we can better characterize vascular microenvironment mechanics in health and disease. Recent advances in material sciences and stem cell biology enable us to accurately recapitulate the complex and dynamic ECM mechanical microenvironment for in vitro studies. These biomimetic approaches help us understand the signaling pathways in disease pathologies, identify therapeutic targets, build tissue replacement and activate tissue regeneration. This Review analyzes how ECM mechanics regulate vascular homeostasis and dysfunction. We highlight approaches to examine ECM mechanics at tissue and cellular levels, focusing on how mechanical interactions between cells and the ECM regulate vascular phenotype, especially under certain pathological conditions. Finally, we explore the development of biomaterials to emulate, measure and alter the physical microenvironment of pathological ECM to understand cell-ECM mechanical interactions toward the development of therapeutics., (© 2023. Springer Nature Limited.)

Fruit from the Prunus mume tree is a traditional food in Japan. Recently, bainiku-ekisu, an infused juice concentrate of Japanese Prunus mume, is attracting attention as a health promoting supplement. Angiotensin II (Ang II) plays a central role in development of hypertension. It has been reported that bainiku-ekisu treatment attenuates the growth-promoting signaling induced by Ang II in vascular smooth muscle cells. However, whether bainiku-ekisu has any effect on an animal model of hypertension remains unknown. Therefore, this study was designed to explore the potential anti-hypertensive benefit of bainiku-ekisu utilizing a mouse model of hypertension with Ang II infusion. Male C57BL/6 mice were infused with Ang II for 2 weeks and given 0.1% bainiku-ekisu containing water or normal water for 2 weeks with blood pressure evaluation. After 2 weeks, mice were euthanized, and the aortas were collected for evaluation of remodeling. Aortic medial hypertrophy was observed in control mice after Ang II infusion, which was attenuated in bainiku-ekisu group with Ang II infusion. Bainiku-ekisu further attenuated aortic induction of collagen producing cells and immune cell infiltration. Development of hypertension induced by Ang II was also prevented by bainiku-ekisu. Echocardiograph indicated protection of Ang II-induced cardiac hypertrophy by bainiku-ekisu. In vascular fibroblasts, bainiku-ekisu attenuated vascular cell adhesion molecule-1 induction, an endoplasmic reticulum stress marker, inositol requiring enzyme-1α phosphorylation, and enhancement in glucose consumption in response to Ang II. In conclusion, Bainiku-ekisu prevented Ang II-induced hypertension and inflammatory vascular remodeling. Potential cardiovascular health benefit to taking bainiku-ekisu should be further studied., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Moyamoya disease (MMD) is characterized by frequent migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in the intima layer of blood vessels. However, the underlying mechanism is unclear. Toll-like receptor (TLR) 7 is abundantly expressed in smooth muscle cells (SMCs) in multiple vascular diseases, which might be linked to the disease-associated vascular remodeling. In the present study, the expression of TLR7 in MMD vessels was examined using the superficial temporal artery (STA) and middle cerebral artery (MCA) from MMD patients. Furthermore, the effect of TLR7 activation on the VSMC phenotype switch in vitro and vascular remodeling in vivo was assessed using a 9.4Tesla MRI. Our results demonstrated that the TLR7 and microRNA Let-7c expression are upregulated in VSMCs and the plasma of MMD patients, respectively. Additionally, TLR7 stimulation by Let-7c or Imiquimod induces a synthetic phenotype switch in VSMCs. Mechanistic studies revealed that Akt/mTOR signaling is responsible for this TLR-induced VSMC phenotypic switch. The Let-7c or Imiquimod treatment also resulted in reduced blood flow of internal carotid arteries (ICAs) in an in vivo model, while TLR7 inhibition attenuated the ICA stenosis. Besides, Let-7c was also found to be elevated in the hypoxic endothelial cells. Taken together, our study demonstrates that Let-7c released by endothelial cells under hypoxic conditions may activate TLR7 on VSMCs, ultimately leading to the phenotype switch and vascular wall remodeling. These findings thus elucidate the putative mechanisms underlying progressive stenosis of blood vessels in MMD and provide prospective therapeutic targets for further exploration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypoxic pulmonary hypertension (HPH) is a life-threatening disease that occurs due to a lack of oxygen in the lungs, leading to an increase in pulmonary vascular resistance, right ventricular failure, and ultimately death. HPH is a multifactorial disorder that involves multiple molecular pathways, making it a challenge for clinicians to identify effective therapies. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPH pathogenesis by proliferating, resisting apoptosis, and promoting vascular remodelling. Curcumin, a natural polyphenolic compound, has shown potential as a therapeutic agent for HPH by reducing pulmonary vascular resistance, inhibiting vascular remodelling, and promoting apoptosis of PASMCs. Regulation of PASMCs could significantly inhibits HPH. However, curcumin has the disadvantages of poor solubility and low bioavailability, and its derivative WZ35 has better biosafety. Here, Cu-based metal organic frameworks (MOF Cu ) was fabricated to encapsulate the curcumin analogue WZ35 (MOF Cu @WZ35) for the inhibition of PASMCs proliferation. The authors found that the MOF Cu @WZ35 could promote the death of PASMCs. Furthermore, the authors believed that this drug delivery system will effectively alleviate the HPH., (© 2023 The Authors. IET Nanobiotechnology published by John Wiley & Sons Ltd.)

Hypoxic pulmonary hypertension (HPH) is a complicated vascular disorder characterized by diverse mechanisms that lead to elevated blood pressure in pulmonary circulation. Recent evidence indicates that HPH is not simply a pathological syndrome but is instead a complex lesion of cellular metabolism, inflammation, and proliferation driven by the reprogramming of gene expression patterns. One of the key mechanisms underlying HPH is hypoxia, which drives immune/inflammation to mediate complex vascular homeostasis that collaboratively controls vascular remodeling in the lungs. This is caused by the prolonged infiltration of immune cells and an increase in several pro-inflammatory factors, which ultimately leads to immune dysregulation. Hypoxia has been associated with metabolic reprogramming, immunological dysregulation, and adverse pulmonary vascular remodeling in preclinical studies. Many animal models have been developed to mimic HPH; however, many of them do not accurately represent the human disease state and may not be suitable for testing new therapeutic strategies. The scientific understanding of HPH is rapidly evolving, and recent efforts have focused on understanding the complex interplay among hypoxia, inflammation, and cellular metabolism in the development of this disease. Through continued research and the development of more sophisticated animal models, it is hoped that we will be able to gain a deeper understanding of the underlying mechanisms of HPH and implement more effective therapies for this debilitating disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ye, Xu and Wuren.)

Background: Vascular remodelling during pulmonary hypertension (PH) is characterized by the phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs). Swietenine (Swi), extracted from the seeds of traditional medicine Swietenia mahagoni, has been used to treat cardiac remodelling, but the effect of Swi on PH is unknown. This study aims to evaluate the effect of Swi on hypoxia-induced phenotypic transformation of PASMCs in experimental PH., Methods: In our research, C57BL/6 mice were treated with SU5416 and exposed to hypoxia for 4 weeks to establish HySu-PH model. Mice in the Swi treatment group were subjected to HySu with daily administration of Swi. Hemodynamic parameters, echocardiography, and degree of vascular muscularization were measured to evaluate the PH model. Proliferation of PASMC was assessed by Ki67 and EdU assay. Cell migration was detected by wound-healing assay. Mitophagy levels were evaluated by mito-tracker and lyso-tracker, autophagic flux, and protein expression of Pink1 and Lc3 II. The molecular docking was used to validate the interaction of Swi with Nrf2. Immunofluorescence and immunohistochemical staining were applied to determine the subcellular localization of Nrf2., Results: The results showed that Swi attenuated hypoxia-induced increase of right ventricle systolic pressure, Fulton index, and vascular remodelling and decreased PASMC proliferation, migration, and enhanced mitophagy. Furthermore, the interaction of Swi with Nrf2 promoted the translocation of Nrf2 into the nucleus, resulting in the induction of Pink1., Conclusions: This study demonstrates that Swi prevents vascular remodelling in experimental PH through inhibition of phenotypic transformation and hyperproliferation of PASMCs caused by reversing hypoxia-induced inhibition of mitophagy., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis; however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalysed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). This study investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH., Methods and Results: Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry. ATIC expression was assessed in platelet-derived growth factor-treated PASMCs and in the lungs of PH rodents and patients with pulmonary arterial hypertension. Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in both hypoxia- and lung interleukin-6/hypoxia-induced murine PH. ATIC-mediated DNPS at the mRNA, protein, and enzymatic activity levels were increased in platelet-derived growth factor-treated PASMCs or PASMCs from PH rodents and patients with pulmonary arterial hypertension. In cultured PASMCs, ATIC knockdown decreased DNPS and nucleic acid DNA/RNA synthesis, and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodelling and inhibited the development and progression of both hypoxia- and lung IL-6/hypoxia-induced PH in mice., Conclusion: Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNA/RNA, reducing PASMC proliferation and pulmonary vascular remodelling and ameliorating the development and progression of PH., Competing Interests: Conflict of interest statement All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypoxia-induced pulmonary hypertension (HPH) is a progressive and lethal disease characterized by the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) and obstructive vascular remodelling. Previous research demonstrated that Breg cells were involved in the pathogenesis of pulmonary hypertension. This work aimed to evaluate the regulatory function of Breg cells in HPH. HPH mice model were established and induced by exposing to chronic hypoxia for 21 days. Mice with HPH were treated with anti-CD22 or adoptive transferred of Breg cells. The coculture systems of Breg cells with CD4 + T cells and Breg cells with PASMCs in vitro were constructed. Lung pathology was evaluated by HE staining and immunofluorescence staining. The frequencies of Breg cells, Tfh cells and Tfr cells were analysed by flow cytometry. Serum IL-21 and IL-10 levels were determined by ELISA. Protein levels of Blimp-1, Bcl-6 and CTLA-4 were determined by western blot and RT-PCR. Proliferation rate of PASMCs was measured by EdU. Compared to the control group, mean PAP, RV/(LV + S) ratio, WA% and WT% were significantly increased in the model group. Anti-CD22 exacerbated abnormal hemodynamics, pulmonary vascular remodelling and right ventricle hypertrophy in HPH, which ameliorated by adoptive transfer of Breg cells into HPH mice. The proportion of Breg cells on day 7 induced by chronic hypoxia was significantly higher than control group, which significantly decreased on day 14 and day 21. The percentage of Tfh cells was significantly increased, while percentage of Tfr cells was significantly decreased in HPH than those of control group. Anti-CD22 treatment increased the percentage of Tfh cells and decreased the percentage of Tfr cells in HPH mice. However, Breg cells restrained the Tfh cells differentiation and expanded Tfr cells differentiation in vivo and in vitro. Additionally, Breg cells inhibited the proliferation of PASMCs under hypoxic condition in vitro. Collectively, these findings suggested that Breg cells may be a new therapeutic target for modulating the Tfh/Tfr immune balance in HPH., (© 2022 John Wiley & Sons Ltd.)