Age-related Vascular Diseases Research Articles

Ghrelin Expression in Atherosclerotic Plaques and Perivascular Adipose Tissue: Implications for Vascular Inflammation in Peripheral Artery Disease.

Atherosclerosis, a leading cause of peripheral artery disease (PAD), is driven by lipid accumulation and chronic inflammation within arterial walls. Objectives: This study investigates the expression of ghrelin, an anti-inflammatory peptide hormone, in plaque morphology and inflammation in patients with PAD, highlighting its potential role in age-related vascular diseases and metabolic syndrome. Methods: The analysis specifically focused on the immunohistochemical expression of ghrelin in atherosclerotic plaques and perivascular adipose tissue (PVAT) from 28 PAD patients. Detailed immunohistochemical staining was performed to identify ghrelin within these tissues, comparing its presence in various plaque types and assessing its association with markers of inflammation and macrophage polarization. Results: Significant results showed a higher prevalence of calcification in fibro-lipid plaques (63.1%) compared to fibrous plaques, with a notable difference in inflammatory infiltration between the two plaque types (p = 0.027). Complicated plaques exhibited increased ghrelin expression, suggesting a modulatory effect on inflammatory processes, although this did not reach statistical significance. The correlation between ghrelin levels and macrophage presence, especially the pro-inflammatory M1 phenotype, indicates ghrelin's involvement in the inflammatory dynamics of atherosclerosis. Conclusions: The findings propose that ghrelin may influence plaque stability and vascular inflammation, pointing to its therapeutic potential in managing atherosclerosis. The study underlines the necessity for further research to clarify ghrelin's impact on vascular health, particularly in the context of metabolic syndrome and age-related vascular alterations.

ISOCITRATE DEHYDROGENASE 2 INHIBITION INDUCES ENDOTHELIAL SENESCENCE BY SUPPRESSION OF MITOPHAGY AND INCREASED ROS PRODUCTION

Objective: Endothelial senescence impairs vascular function and thus is a primary event of age-related vasculature diseases. Isocitrate dehydrogenase 2 (IDH2) plays an important role in inducing alpha-ketoglutarate (alpha-KG) production and preserving mitochondrial function. However, the mechanism and regulation of IDH2 in endothelial senescence have not been elucidated. Design and method: We confirmed vascular endothelial senescence using human umbilical vein endothelial cells(HUVECs) and IDH2 Knockout mouse. Results: We demonstrated that downregulation of IDH2 induced accumulation of miR-34b/c, which impaired mitophagy and elevated mitochondrial reactive oxygen species (ROS) levels by inhibiting mitophagy-related markers (PTEN-induced putative kinase 1 (PINK1), Parkin, LC-II/LC3-I, and p62) and attenuating Sirtuin deacetylation 3 (Sirt3) expression. The mitochondrial dysfunction induced by IDH2 deficiency disrupted cell homeostasis and the cell cycle and led to endothelial senescence. However, miR-34b/c inhibition or alpha-KG supplementation restored Sirt3, PINK1, Parkin, LC-II/LC3-I, p62, and mitochondrial ROS levels, subsequently alleviating endothelial senescence. Conclusions: This study demonstrates that IDH2 deficiency is critical for the suppression of alpha-KG levels, which induced endothelial senescence via miR-34b/c inhibition of mitophagy and mitochondrial ROS elevation in endothelial cells (Figure 7). Therefore, the IDH2/alpha-KG/miR-34b/c axis may provide a potential therapeutic target for age-related vascular diseases.

Hypertension facilitates age-related diseases. ~ Is hypertension associated with a wide variety of diseases?~.

Hypertension, a disease whose prevalence increases with age, induces pathological conditions of ischemic vascular disorders such as cerebral infarction and myocardial infarction due to accelerated arteriosclerosis and circulatory insufficiency of small arteries and sometimes causes hemorrhagic conditions such as cerebral hemorrhage and ruptured aortic aneurysm. On the other hand, as it is said that aging starts with the blood vessels, impaired blood flow associated with vascular aging is the basis for the development of many pathological conditions, and ischemic changes in target organs associated with vascular disorders result in tissue dysfunction and degeneration, inducing organ hypofunction and dysfunction. Therefore, we hypothesized that hypertension is associated with all age-related vascular diseases, and attempted to review the relationship between hypertension and diseases for which a relationship has not been previously well reported. Following our review, we hope that a collaborative effort to unravel age-related diseases from the perspective of hypertension will be undertaken together with experts in various specialties regarding the relationship of hypertension to all pathological conditions.

Functional, Structural and Proteomic Effects of Ageing in Resistance Arteries.

The normal ageing process affects resistance arteries, leading to various functional and structural changes. Systolic hypertension is a common occurrence in human ageing, and it is associated with large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, a progressive elevation in the mean arterial pressure is evidenced by clinical and epidemiological data as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. The dysregulation of calcium entry channels (L-type, T-type, and TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to the age-related dysregulation of myogenic tone. Flow-mediated vasodilation, a hallmark of endothelial function, is compromised in ageing. This endothelial dysfunction is related to increased oxidative stress, lower nitric oxide bioavailability, and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall that is typically observed in conjunction with outward remodeling (in normotension), or as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of actin cytoskeletal components, and extracellular matrix fiber proteins. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation play substantial roles in age-related vascular dysfunction. Due to its role in the regulation of vascular tone and structural proteins, the RhoA/Rho-kinase pathway is an important target in age-related vascular dysfunction and diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance the overall vascular health.

Abstract 15041: Single-Cell RNA Sequencing Reveals Four Distinctive Endothelial Subpopulations Through Mouse Endothelial Aging

Introduction: Endothelial cell (EC) dysfunction is a hallmark of vascular aging, contributing to age-related vascular diseases. Elucidating EC aging at the single cell level has significant scientific and therapeutic potential. Research Question: What is the landscape of EC aging at the single cell level? Methods: Mouse aortas were harvested from 1-, 10-, and 20 month-old mice (n=2 males and 2 females at each time point). Pooled single-cell suspensions were prepared, and PECAM1+ cells were enriched by magnetic-activated cell sorting. Results: Single cell RNA sequencing revealed 879 ECs, categorized into six subpopulations (EC 1-6). Of the three canonical EC markers ( Pecam1 , Cdh5, and Kdr ) EC1 and 2 showed higher expression of Pecam1 , whereas EC3 and 4 showed higher expression of Cdh5 and Kdr . ECs from young (1 month-old), middle-aged (10 month-old), and elderly mice (20 month-old) were enriched in EC1, EC3, and EC4, respectively. Gene regulatory network analysis identified specific regulons for each EC subcluster. EC1 displayed progenitor-like features ( Isl1 as one of the top regulons, Procr and Cd34 as highly expressed genes) with high angiogenic potential ( Twist1 as one of the top regulons, Timp2 , Mmp14 , and Mmp2 as highly expressed genes) and the longest G1 phase suggesting its quiescence. EC3 cells exhibited high proliferative status demonstrated by G2M or S phase, accompanied by upregulation of stress-responsive TF Atf3 and NF-κB family members. EC4 demonstrated pronounced Pparg regulon activity. Genes directly regulated by Pparg ( Scarb1 and Cd36 ), and genes involved in fatty acid metabolism and atherogenesis ( Tcf15 , Fabp4 , Gpihbp1 , Lpl , and Meox2) were highly expressed in EC4 and EC3. Conclusions: Our analysis identified four distinct EC subpopulations through the aging process of mouse aortic ECs: EC1, Pecam1 h progenitor-like EC; EC2, Pecam1 h common EC; EC3, Cdh5 h Kdr h inflammatory atherogenic EC; and EC4, Cdh5 h Kdr h non-inflammatory atherogenic EC.

Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.

Cellular senescence is closely linked to endothelial dysfunction, a key factor in age-related vascular diseases. Senescent endothelial cells exhibit a proinflammatory phenotype known as SASP, leading to chronic inflammation (inflammaging) and vascular impairments. Albeit in a state of permanent growth arrest, senescent cells paradoxically display a high metabolic activity. The relationship between metabolism and inflammation is complex and varies across cell types and senescence inductions. While some cell types shift towards glycolysis during senescence, others favor oxidative phosphorylation (OXPHOS). Despite the high availability of oxygen, quiescent endothelial cells (ECs) tend to rely on glycolysis for their bioenergetic needs. However, there are limited data on the metabolic behavior of senescent ECs. Here, we characterized the metabolic profiles of young and senescent human umbilical vein endothelial cells (HUVECs) to establish a possible link between the metabolic status and the proinflammatory phenotype of senescent ECs. Senescent ECs internalize a smaller amount of glucose, have a lower glycolytic rate, and produce/release less lactate than younger cells. On the other hand, an increased fatty acid oxidation activity was observed in senescent HUVECs, together with a greater intracellular content of ATP. Interestingly, blockade of glycolysis with 2-deoxy-D-glucose in young cells resulted in enhanced production of proinflammatory cytokines, while the inhibition of carnitine palmitoyltransferase 1 (CPT1), a key rate-limiting enzyme of fatty acid oxidation, ameliorated the SASP in senescent ECs. In summary, metabolic changes in senescent ECs are complex, and this research seeks to uncover potential strategies for modulating these metabolic pathways to influence the SASP.

Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies.

Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.

Unravelling the impact of aging on the human endothelial lncRNA transcriptome.

The incidence and prevalence of cardiovascular disease is highest among the elderly. There is a need to further understand the mechanisms behind endothelial cell aging in order to achieve vascular rejuvenation and minimize the onset of age-related vascular diseases. Long non-coding RNAs (lncRNAs) have been proposed to regulate numerous processes in the human genome, yet their function in vascular aging and their therapeutic potential remain largely unknown. This is primarily because the majority of studies investigating the impact of aging on lncRNA expression heavily rely on in vitro studies based on replicative senescence. Here, using a unique collection of young and aged endothelial cells isolated from native human arteries, we sought to characterize the age-related alterations in lncRNA expression profiles. We were able to detect a total of 4463 lncRNAs expressed in the human endothelium from which ∼17% (798) were altered in advanced age. One of the most affected lncRNAs in aging was the primate-specific, Prostate Cancer Associated Transcript (PCAT) 14. In our follow up analysis, using single molecule RNA FISH, we showed that PCAT14 is relatively abundant, localized almost exclusively in the nucleus of young endothelial cells, and silenced in the aged endothelium. Functionally, our studies proposed that downregulation of PCAT14 alters endothelial cell transcription profile and cell functions including endothelial cell migration, sprouting and inflammatory responses in vitro. Taken together, our data highlight that endothelial cell aging correlates with altered expression of lncRNAs, which could impair the endothelial regenerative capacity and enhance inflammatory phenotypes.

Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging.

Aging causes a progressive decline in the structure and function of organs. With advancing age, an accumulation of senescent endothelial cells (ECs) contributes to the risk of developing vascular dysfunction and cardiovascular diseases, including hypertension, diabetes, atherosclerosis, and neurodegeneration. Senescent ECs undergo phenotypic changes that alter the pattern of expressed proteins, as well as their morphologies and functions, and have been linked to vascular impairments, such as aortic stiffness, enhanced inflammation, and dysregulated vascular tone. Numerous molecules and pathways, including sirtuins, Klotho, RAAS, IGFBP, NRF2, and mTOR, have been implicated in promoting EC senescence. This review summarizes the molecular players and signaling pathways driving EC senescence and identifies targets with possible therapeutic value in age-related vascular diseases.

Inflammatory Molecular Mediators and Pathways Involved in Vascular Aging and Stroke: A Comprehensive Review.

There is an increase in the incidence of cardiovascular diseases with aging and it is one of the leading causes of death worldwide. The main cardiovascular pathologies include atherosclerosis, myocardial infarction, hypertension and stroke. Chronic inflammation is one of the significant contributors to the age-related vascular diseases. Therefore, it is important to understand the molecular mechanisms of the persistent inflammatory conditions occurring in the blood vessels as well as the signaling pathways involved. Herein, we performed an extant search of literature involving PubMed, ISI, WoS and Scopus databases for retrieving all relevant articles with the most recent findings illustrating the potential role of various inflammatory mediators along with their proposed activated pathways in the pathogenesis and progression of vascular aging. We also highlight the major pathways contributing to age-related vascular disorders. The outlined molecular mechanisms, pathways and mediators of vascular aging represent potential drug targets that can be utilized to inhibit and/or slow the pathogenesis and progression of vascular aging.

Caloric restriction enhances vascular tone of cerebral and mesenteric resistance arteries in aged rats

Vascular changes of tone and biomechanical properties induced by ageing increase the risk for cardiovascular diseases. Caloric restriction (CR) has been shown to protect against cardiovascular diseases and improve endothelial dysfunction in cerebral resistance arteries.We hypothesise that CR will enhance vascular tone and structural properties of cerebral resistance arteries and exert comparable beneficial effects on the systemic vasculature of aged rat model.Eighteen-month-old male Sprague-Dawley rats were feed either ad libitum or restricted to 60 % of calorie consumption up to 24 months of age, when body weight (BW) measurements were taken and functional and structural properties of resistance arteries were assessed using a pressure myograph.In cerebral arteries, CR increased myogenic tone (p < 0.001) and distensibility (p < 0.01) in response to intraluminal pressure and concentration-dependent constriction to KCl (p < 0.001). In mesenteric arteries constriction in response to KCl was increased (p < 0.0001) and wall thickness reduced (p < 0.01) in CR rats. BW was reduced (p < 0.0001) in FR rats.Our findings demonstrate that CR improves vascular tone of resistance arteries regardless the type of stimulus and independently of the vascular bed. CR may be a beneficial dietary approach to prevent age-related vascular diseases.

The aging endothelium.

Cellular senescence is now recognized as one of the hallmarks of aging. Herein, we examine current findings on senescence of the vascular endothelium and its impacts on age-related vascular diseases. Endothelial senescence can result in systemic metabolic changes, implicating senescence in chronic diseases such as diabetes, obesity and atherosclerosis. Senolytics, drugs that eliminate senescent cells, afford new therapeutic strategies for control of these chronic diseases.

Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.

Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.

Cell senescence: basic mechanisms and the need for computational networks in vascular ageing

This review seeks to provide an update of the mechanisms of vascular cell senescence, from newly identified molecules to arterial ageing phenotypes, and finally to present a computational approach to connect these selected proteins in biological networks. We will discuss current key signalling and gene expression pathways by which these focus proteins and networks drive normal and accelerated vascular ageing. We also review the possibility that senolytic drugs, designed to restore normal cell differentiation and function, could effectively treat multiple age-related vascular diseases. Finally, we discuss how cell senescence is both a cause and a consequence of vascular ageing because of the possible feedback controls between identified networks.

‘Smart’ wound dressings for advanced wound care: a review

Hard-to-heal wounds are a common side-effect of diabetes, obesity, pressure ulcers and age-related vascular diseases, the incidences of which are growing worldwide. The increasing financial burden of hard-to-heal wounds on global health services has provoked technological research into improving wound diagnostics and therapeutics via 'smart' dressings, within which elements such as microelectronic sensors, microprocessors and wireless communication radios are embedded. This review highlights the progress being made by research groups worldwide in producing 'smart' wound device prototypes. Significant advances have been made, for example, flexible substrates have replaced rigid circuit boards, sensors have been printed on commercial wound dressing materials and wireless communication has been demonstrated. Challenges remain, however, in the areas of power supply, disposability, low-profile components, multiparametric sensing and seamless device integration in commercial wound dressings.

MTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.

Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases.

Aging is associated with increased oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of a wide range of diseases affecting the circulatory system in older adults. There is growing evidence that in addition to increased production of reactive oxygen species (ROS), aging critically impairs pathways determining cellular resilience to oxidative stressors. In young organisms, the evolutionarily conserved nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis and promotes a youthful cellular phenotype by regulating the transcription of an array of cytoprotective (antioxidant, pro-survival, anti-inflammatory and macromolecular damage repair) genes. A critical mechanism by which increased ROS production and Nrf2 dysfunction promote vascular aging and exacerbate pathogenesis of age-related vascular diseases is induction of cellular senescence, an evolutionarily conserved cellular stress response mechanism. Senescent cells cease dividing and undergo distinctive phenotypic alterations, contributing to impairment of angiogenic processes, chronic sterile inflammation, remodeling of the extracellular matrix, and barrier dysfunction. Herein, we review mechanisms contributing to dysregulation of Nrf2-driven cytoprotective responses in the aged vasculature and discuss the multifaceted role of Nrf2 dysfunction in the genesis of age-related pathologies affecting the circulatory system, including its role in induction of cellular senescence. Therapeutic strategies that restore Nrf2 signaling and improve vascular resilience in aging are explored to reduce cardiovascular mortality and morbidity in older adults.

Hot Water Extract of Loliolus beka Meat Attenuates H2O2-Induced Damage in Human Umbilical Vein Endothelial Cells.

Blood vessels become less flexible with senescence; arteries narrow and become less flexible, disturbing blood circulation in aging and other vascular diseases. Mechanistically, vascular senescence plays an important role in the pathogenesis of normal aging and age-related vascular diseases. Vascular senescence also causes vascular dysfunction, resulting in damage to the vessel wall. Vascular aging involves the senescence of endothelial cells. Hydrogen peroxide is widely used to achieve oxidative stress-induced premature senescence. Here, we investigated the protective effects of a hot water extract of Loliolus beka meat (LBM) against H2O2-exposed HUVECs, a human umbilical vein endothelial cells line. The hot water extract of LBM protected cells against H2O2-induced cytotoxicity while reducing the expression of senescence markers, including β-galactosidase, p53, and p21. In addition, the hot water extract of LBM protected against H2O2-induced DNA damage. These findings suggest that the hot water extract of LBM protects HUVECs from H2O2-induced senescence by preventing cellular damage. LBM serve as a supplement or natural food with benefits against vascular disease.

Loss of miR-146b-3p Inhibits Perivascular Adipocyte Browning with Cold Exposure During Aging.

Pathological changes of the perivascular adipose tissue (PVAT) are directly associated with increased risk of age-related vascular diseases. MicroRNAs regulate adipocyte biological functions including adipogenic differentiation and white adipocyte browning. The present study aims to determine whether miR-146b-3p is involved in the regulation of perivascular adipocyte browning during aging. We utilized a cold-induced animal model to investigate the effect of aging on perivascular adipocyte browning. We also detected the miR-146b-3p expression in the PVAT of young or old mice after cold stimulus. We further investigated the role of miR-146b-3p in regulating perivascular adipocyte browning in vitro and in vivo via administrating miRNA mimics or inhibitors. Old mice showed decrease of perivascular adipocyte browning and downregulation of miR-146b-3p expression in the PVAT after cold stimulus. Oil red O staining and qPCR indicated that aging perturbed preadipocyte to brown adipocyte differentiation, and expression of miR-146b-3p gradually increased during differentiation. MiR-146b-3p inhibitors blocked brown adipocyte differentiation in young preadipocytes, whereas miR-146b-3p mimics rescued the differentiation of the old preadipocytes. Finally, miR-146b-3p knocks down inhibited perivascular adipocyte browning in young mice after cold stimulus. Aging inhibits perivascular adipocyte browning, and loss of miR-146b-3p is a potential regulator for this process.

Double-Face of Vasohibin-1 for the Maintenance of Vascular Homeostasis and Healthy Longevity.

The structural and functional integrity of endothelium is essential for the maintenance of vascular health. Vasohibin-1 (VASH1), originally isolated as an endothelium-derived angiogenesis inhibitor, has another function to promote stress tolerance of endothelial cells (ECs), and these functions are critical for the maintenance of vascular homeostasis preventing both pathological angiogenesis and stress-induced vascular diseases. The expression of VASH1 is downregulated during replicative senescence of ECs by the alteration of microRNA expression, and this age-associated downregulation of VASH1 might be a risk of deterioration of vascular homeostasis and age-related vascular diseases. Contrary to this expectation, the lack of Vash1 gene in mice exhibited healthy longevity. Thus, VASH1 has double-face for the maintenance of vascular homeostasis and healthy longevity. This feature of VASH1 and its mechanism will be described in this mini review.