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Location of pericytes and vascular smooth muscle cells in blood vessels. Smooth muscle cells continuously surround endothelial cells in arteries, arterioles, veins, and venules. Pericytes form a discontinuous layer surrounding endothelial cells in capillaries.
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Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of di...
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Context 1
... muscle cells (SMCs) are circumferentially arranged to make up the tunica media layer of all vessels except capillaries. Capillaries are not lined with SMCs but have a discontinuous layer of cells known as pericytes (Figure 1). The tunica adventitia is the outermost, supportive layer primarily composed of fibroblasts, extracellular matrix and progenitor cells [3]. ...
Context 2
... muscle cells (SMCs) are circumferentially arranged to make up the tunica media layer of all vessels except capillaries. Capillaries are not lined with SMCs but have a discontinuous layer of cells known as pericytes (Figure 1). The tunica adventitia is the outermost, supportive layer primarily composed of fibroblasts, extracellular matrix and progenitor cells [3]. ...
Context 3
... muscle cells (SMCs) are circumferentially arranged to make up the tunica media layer of all vessels except capillaries. Capillaries are not lined with SMCs but have a discontinuous layer of cells known as pericytes (Figure 1). The tunica adventitia is the outermost, supportive layer primarily composed of fibroblasts, extracellular matrix and progenitor cells [3]. ...
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Macrophages are heterogeneous and plastic cells, able to adapt their phenotype and functions to changes in the microenvironment. They are involved in several homeostatic processes and also in many human diseases, including atherosclerosis, where they participate in all the stages of the disease. For these reasons, macrophages have been studied exte...
Citations
... In larger vessels, the media is composed of multiple layers of mural cells, including vascular smooth muscle cells in arteries and veins and pericytes in the wall of microcirculatory blood vessels. The adventitia comprises fibroblasts and extracellular matrix that provide structural support to the vessels, as well as small vessels (vasa vasorum) and nerve endings [3] (graphical summary: Figure 1). ...
Endothelial cells (ECs) line the inner surface of all blood vessels and form a barrier that facilitates the controlled transfer of nutrients and oxygen from the circulatory system to surrounding tissues. Exposed to both laminar and turbulent blood flow, ECs are continuously subject to differential mechanical stimulation. It has been well established that the shear stress associated with laminar flow (LF) is atheroprotective, while shear stress in areas with turbulent flow (TF) correlates with EC dysfunction. Moreover, ECs show metabolic adaptions to physiological changes, such as metabolic shifts from quiescence to a proliferative state during angiogenesis. The AMP-activated protein kinase (AMPK) is at the center of these phenomena. AMPK has a central role as a metabolic sensor in several cell types. Moreover, in ECs, AMPK is mechanosensitive, linking mechanosensation with metabolic adaptions. Finally, recent studies indicate that AMPK dysregulation is at the center of cardiovascular disease (CVD) and that pharmacological targeting of AMPK is a promising and novel strategy to treat CVDs such as atherosclerosis or ischemic injury. In this review, we summarize the current knowledge relevant to this topic, with a focus on shear stress-induced AMPK modulation and its consequences for vascular health and disease.
... Perivascular cells include pericytes, vascular smooth muscle cells, mesangial cells and interstitial fibroblasts 16 . Mural cells comprise both smooth muscle cells and pericytes, and contribute to the regulation of blood pressure and maintenance of the structural integrity of the vascular wall 17 . Mesangial cells, which are pericyte-like smooth muscle cells that support glomerular capillaries, are derived from a common mesenchymal stromal precursor that also gives rise to other kidney pericytes 18 . ...
Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in preserving kidney homeostasis as they maintain microvascular networks by stabilizing the vasculature and regulating capillary constriction. A subset of kidney perivascular cells can also produce and secrete erythropoietin; this ability can be enhanced with hypoxia-inducible factor-prolyl hydroxylase inhibitors, which are used to treat anaemia in chronic kidney disease. In the pathophysiological state, kidney perivascular cells contribute to the progression of kidney fibrosis, partly via transdifferentiation into myofibroblasts. Moreover, perivascular cells are now recognized as major innate immune sentinels in the kidney that produce pro-inflammatory cytokines and chemokines following injury. These mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis. The crosstalk between perivascular cells and tubular epithelial, immune and endothelial cells is therefore a key process in physiological and pathophysiological states. Here, we examine the multiple roles of kidney perivascular cells in health and disease, focusing on the latest advances in this field of research.
... MCs are subdivided into pericytes and vascular smooth-muscle cells (vSMC) ( Figure 1A). In capillaries and post-capillary venules, pericytes are the only abundant MC type, while in larger-caliber vessels such as arteries, veins, and arterioles, vSMCs are majorly found [9][10][11]. In the mouse whole-mount retina, MCs are widely expressed, together with endothelial cells ( Figure 1B). ...
Serum response factor (SRF) controls the expression of muscle contraction and motility genes in mural cells (MCs) of the vasculature. In the retina, MC-SRF is important for correct angio-genesis during development and the continuing maintenance of the vascular tone. The purpose of this study was to provide further insights into the effects of MC SRF deficiency on the vasculature and function of the mature retina in Srf iMCKO mice that carry a MC-specific deletion of Srf. Retinal morphology and vascular integrity were analyzed in vivo via scanning laser ophthalmoscopy (SLO), angiography, and optical coherence tomography (OCT). Retinal function was evaluated with full-field electroretinography (ERG). We found that retinal blood vessels of these mutants exhibited different degrees of morphological and functional alterations. With increasing severity, we found vascular bulging, the formation of arteriovenous (AV) anastomoses, and ultimately, a retinal detachment (RD). The associated irregular retinal blood pressure and flow distribution eventually induced hypoxia, indicated by a negative ERG waveform shape. Further, the high frequency of interocular differences in the phenotype of individual Srf iMCKO mice points to a secondary nature of these developments far downstream of the genetic defect and rather dependent on the local retinal context.
... VSMCs are characterized by remarkable heterogeneity and plasticity, and the ability to transdifferentiate into different cell types. Some of these transdifferentiated states can be protective whereas others can contribute to the pathogenesis and progression of several disorders [34]. For instance, analysing the brains of Alzheimer's patients and animal models, VSMCs showed dramatic phenotypic transitions under AD-like conditions, adopting a pro-inflammatory phenotype with decreased contractile markers, which correlates with Tau accumulation in brain arterioles [35]. ...
The neurovascular system (NVS) is a complex anatomic-functional unit that synergically works to maintain organs/tissues homeostasis of the entire body. NVS alterations have recently emerged as a common distinct feature in the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Despite their undeniable involvement, neurovascular signalling pathways remain still far unknown in ALS. This review underlines the importance of endothelial, mural, and fibroblast cells as novel targets for ALS investigation and identifies in the interplay between neuronal and vascular systems the way to disclose novel molecular mechanisms behind the pathogenesis of ALS.
... Further work in this field could address both CMDs and AD as a single entity rather than two different disorders and "kill two birds with one stone" as Motamedi et al. wrote in [105]; also see [1-4,37,106 -110]. As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" ...
... Further work in this field could address both CMDs and AD as a single entity rather than two different disorders and "kill two birds with one stone" as Motamedi et al. wrote in [105]; also see [1][2][3][4]37,[106][107][108][109][110]. As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" was published, whereby cerebral blood hypoperfusion subsequently lead to AD [114], and revitalized now by [111]. ...
... As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" was published, whereby cerebral blood hypoperfusion subsequently lead to AD [114], and revitalized now by [111]. In the present review, we propose the "vasculometabolic (metabodegenerative) hypothesis of AD." Proving or disproving of it must come with further study. ...
Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer’s disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the “vascular hypothesis of AD” was published and in the present review we propose the “vasculometabolic hypothesis of AD.” We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.
... Further work in this field could address both CMDs and AD as a single entity rather than two different disorders and "kill two birds with one stone" as Motamedi et al. wrote in [105]; also see [1-4,37,106 -110]. As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" ...
... Further work in this field could address both CMDs and AD as a single entity rather than two different disorders and "kill two birds with one stone" as Motamedi et al. wrote in [105]; also see [1][2][3][4]37,[106][107][108][109][110]. As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" was published, whereby cerebral blood hypoperfusion subsequently lead to AD [114], and revitalized now by [111]. ...
... As discussed in [111], clinicians would be able to prescribe to vulnerable patients (identified through genetic analysis or clinical risk stratification) with some CMD drugs that may also exert beneficial effects for neurodegenerative diseases [112,113]. Of note, in 1973 the "vascular hypothesis of AD" was published, whereby cerebral blood hypoperfusion subsequently lead to AD [114], and revitalized now by [111]. In the present review, we propose the "vasculometabolic (metabodegenerative) hypothesis of AD." Proving or disproving of it must come with further study. ...
Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer's disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose-and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the "vascular hypothesis of AD" was published and in the present review we propose the "vasculometabolic hypothesis of AD." We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.
Cardiac aging, particularly cardiac cell senescence, is a natural process that occurs as we age. Heart function gradually declines in old age, leading to continuous heart failure, even in people without a prior history of heart disease. To address this issue and improve cardiac cell function, it is crucial to investigate the molecular mechanisms underlying cardiac senescence. This review summarizes the main mechanisms and key proteins involved in cardiac cell senescence. This review further discusses the molecular modulators of cellular senescence in aging hearts. Furthermore, the discussion will encompass comprehensive descriptions of the key drugs, modes of action and potential targets for intervention in cardiac senescence. By offering a fresh perspective and comprehensive insights into the molecular mechanisms of cardiac senescence, this review seeks to provide a fresh perspective and important theoretical foundations for the development of drugs targeting this condition.
In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+ sensitivity in vascular smooth muscle cells. This review focuses on the potential implication of Na,K-ATPase-dependent intracellular signaling pathways in severe vascular disorders; ischemic stroke, familial migraine, and arterial hypertension. We propose similarity in the detrimental Na,K-ATPase-dependent signaling seen in these pathological conditions. The review includes a retrospective proteomics analysis investigating temporal changes after ischemic stroke. The analysis revealed that the expression of Na,K-ATPase α isoforms is down-regulated in the days and weeks following reperfusion, while downstream Na,K-ATPase-dependent cSrc kinase is up-regulated. These results are important since previous studies have linked the Na,K-ATPase-dependent cSrc signaling to futile recanalization and vasospasm after stroke. The review also explores a link between the Na,K-ATPase and migraine with aura, as reduced expression or pharmacological inhibition of the Na,K-ATPase leads to cSrc kinase signaling up-regulation and cerebral hypoperfusion. The review discusses the role of an endogenous cardiotonic steroid-like compound, ouabain, which binds to the Na,K-ATPase and initiates the intracellular cSrc signaling, in the pathophysiology of arterial hypertension. Currently, our understanding of the precise control mechanisms governing the Na,K-ATPase/cSrc kinase regulation in the vascular wall is limited. Understanding the role of vascular Na,K-ATPase signaling is essential for developing targeted treatments for cerebrovascular disorders and hypertension, as the Na,K-ATPase is implicated in the pathogenesis of these conditions and may contribute to their comorbidity.
Aim:
Under various pathological conditions such as cancer, vascular smooth muscle cells (vSMCs) transit their contractile phenotype into phenotype(s) characterized by proliferation and secretion, a process called vSMC phenotypic transition (vSMC-PT). Notch signaling regulates vSMC development and vSMC-PT. This study aims to elucidate how the Notch signal is regulated.
Main methods:
Gene-modified mice with a SM22α-CreERT2 transgene were generated to activate/block Notch signaling in vSMCs. Primary vSMCs and MOVAS cells were cultured in vitro. RNA-seq, qRT-PCR and Western blotting were used to evaluated gene expression level. EdU incorporation, Transwell and collagen gel contraction assays were conducted to determine the proliferation, migration and contraction, respectively.
Key findings:
Notch activation upregulated, while Notch blockade downregulated, miR-342-5p and its host gene Evl in vSMCs. However, miR-342-5p overexpression promoted vSMC-PT as shown by altered gene expression profile, increased migration and proliferation, and decreased contraction, while miR-342-5p blockade exhibited the opposite effects. Moreover, miR-342-5p overexpression significantly suppressed Notch signaling, and Notch activation partially abolished miR-342-5p-induced vSMC-PT. Mechanically, miR-342-5p directly targeted FOXO3, and FOXO3 overexpression rescued miR-342-5p-induced Notch repression and vSMC-PT. In a simulated tumor microenvironment, miR-342-5p was upregulated by tumor cell-derived conditional medium (TCM), and miR-342-5p blockade abrogated TCM-induced vSMC-PT. Meanwhile, conditional medium from miR-342-5p-overexpressing vSMCs significantly enhanced tumor cell proliferation, while miR-342-5p blockade had the opposite effects. Consistently, in a co-inoculation tumor model, miR-342-5p blockade in vSMCs significantly delayed tumor growth.
Significance:
miR-342-5p promotes vSMC-PT through a negative-feedback regulation of Notch signaling via downregulating FOXO3, which could be a potential target for cancer therapy.
Vascular smooth muscle cells (VSMCs) are the key moderators of cerebrovascular dynamics in response to the brain’s oxygen and nutrient demands. Crucially, VSMCs may provide a sensitive biomarker for neurodegenerative pathologies where vasculature is compromised. An increasing body of research suggests that VSMCs have remarkable plasticity and their pathophysiology may play a key role in the complex process of neurodegeneration. Furthermore, extrinsic risk factors, including environmental conditions and traumatic events can impact vascular function through changes in VSMC morphology. VSMC dysfunction can be characterised at the molecular level both preclinically, and clinically ex vivo. However the identification of VSMC dysfunction in living individuals is important to understand changes in vascular function at the onset and progression of neurological disorders such as dementia, Alzheimer’s disease, and Parkinson’s disease. A promising technique to identify changes in the state of cerebral smooth muscle is cerebrovascular reactivity (CVR) which reflects the intrinsic dynamic response of blood vessels in the brain to vasoactive stimuli in order to modulate regional cerebral blood flow (CBF). In this work, we review the role of VSMCs in the most common neurodegenerative disorders and identify physiological systems that may contribute to VSMC dysfunction. The evidence collected here identifies VSMC dysfunction as a strong candidate for novel therapeutics to combat the development and progression of neurodegeneration, and highlights the need for more research on the role of VSMCs and cerebrovascular dynamics in healthy and diseased states.
