Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases

Abstract

In contrast with the heart, the adult mammalian vasculature retains significant remodelling capacity, dysregulation of which is implicated in disease development. In particular, vascular smooth muscle cells (VSMCs) play major roles in the pathological vascular remodelling characteristic of atherosclerosis, restenosis, aneurysm and pulmonary arterial hypertension. Clonal lineage tracing revealed that the VSMC-contribution to disease results from the hyperproliferation of few pre-existing medial cells and suggested that VSMC-derived cells from the same clone can adopt diverse phenotypes. Studies harnessing the powerful combination of lineage tracing and single-cell transcriptomics have delineated the substantial diversity of VSMC-derived cells in vascular lesions, which are proposed to have both beneficial and detrimental effects on disease severity. Computational analyses further suggest that the pathway from contractile VSMCs in healthy arteries to phenotypically distinct lesional cells consists of multiple, potentially regulatable, steps. A better understanding of how individual steps are controlled could reveal effective therapeutic strategies to minimise VSMC functions that drive pathology whilst maintaining or enhancing their beneficial roles. Here we review current knowledge of VSMC plasticity and highlight important questions that should be addressed to understand how specific stages of VSMC investment and phenotypic diversification are controlled. Implications for developing therapeutic strategies in pathological vascular remodelling are discussed and we explore how cutting-edge approaches could be used to elucidate the molecular mechanisms underlying VSMC regulation.

Vascular smooth muscle cell dysfunction in neurodegeneration

“…Studies have shown that targeting the vascular tissue with drugs may be effective at modulating and/or preventing neurodegenerative disorders such as AD and PD ( Speer and Ratan, 2009 ; Aguilar-Pineda et al, 2021a ). It has also been suggested that intervening during the differentiation, proliferation, and/or migration mechanisms of VSMCs could be a therapeutic strategy to reduce pathological VSMC functions while maintaining their stabilising roles in CBF ( Worssam and Jørgensen, 2021 ). Here, we will review recent insights on VSMC-based therapeutics in vascular pathology and discuss how VSMCs could be targeted to intervene in the development and progression of neurodegenerative disorders.…”

Trilinolein, a Natural Triacylglycerol, Protects Cerebral Ischemia through Inhibition of Neuronal Apoptosis and Ameliorates Intimal Hyperplasia via Attenuation of Migration and Modulation of Matrix Metalloproteinase-2 and RAS/MEK/ERK Signaling Pathway in VSMCs

“…Abnormal VSMC proliferation is associated with the development of cerebrovascular diseases [ 36 ]. PDGF-BB, the most potent cell proliferation and migration stimulator, initiates cellular responses by activating intracellular signal transduction pathways such as mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), leading to VSMC proliferation and migration [ 37 , 38 ].…”

“…The PCNA, as an index of cell proliferation, has been identified by immunofluorescence [ 47 ]. During atherosclerosis and intimal hyperplasia formation, various cytokines and growth factors stimulate VSMC to express MMPs [ 31 , 36 ]. In this study, TriL reduced the severity of intimal hyperplasia induced by carotid-ligation and decreased PCNA expression and PDGF-BB-stimulated VSMC migration.…”

Yohimbine, an α2-Adrenoceptor Antagonist, Suppresses PDGF-BB-Stimulated Vascular Smooth Muscle Cell Proliferation by Downregulating the PLCγ1 Signaling Pathway

“…VSMC proliferation is critical in the pathogenesis of atherosclerosis and associated vascular diseases [ 35 , 36 ]. Abnormal VSMC proliferation can be induced by a multitude of mitogenic factors, among which PDGF-BB is the most potent cell proliferation stimulator that acts through the activation of PDGFR signaling and further signal propagation.…”