ECs in health and disease
Development vs. adulthood
The vasculature forms early during embryo development and is essential for the growth, survival, and function of all organ systems. Its innermost layer, the endothelium, is a major regulator of vessel biology in health and disease.5,22 It consists of a single layer of ECs lining the luminal surface of blood vessels, whereby ECs mediate a complex regulation of the vessel wall. First, embryonic ECs originate from the mesoderm and undergo profound remodelling changes promoting vessel wall formation and organization into a circulatory network.23 Subsequently, ECs acquire site-specific specializations to address distinct structural and biological needs in an organ-specific manner and based on their position along the vasculature or within a specific vascular bed.23–25
The situation is different in adulthood where healthy ECs are mostly in a quiescent state defined by reduced endothelial proliferation, reduced migration, and maintained barrier integrity.26,27 EC homeostasis results from a dynamic balance wherein the endothelium uses paracrine and endocrine factors, alongside autocrine feedback loops, to maintain cell stability and normalcy.28–30 The crosstalk between ECs and bystander cells [e.g. vascular smooth muscle cells (VSMCs) and pericytes] is critical, and the disruption of this cell–cell communication (by direct or indirect interaction) negatively affects vessel homeostasis.31,32
Far from representing merely a physical barrier, ECs participate in sensing circulating factors and responding to a range of intrinsic and extrinsic signals.33 ECs are thereby involved in a wide variety of processes, spanning from regulation of vascular tone, cellular adhesion, migration, coagulation, and vessel wall permeability to inflammatory processes.11 However, imbalances in EC homeostatic functions and failure to recover from noxious stimuli can lead to disease, promoting the reactivation of EndMT.19,20,34,35 Such activation leads to vascular integrity disruption by affecting EC cell–cell adhesion, promoting metalloproteinase (MMPs)-mediated extracellular matrix (ECM) degradation,36,37 and acquisition of migratory and proliferative cellular properties.38,39 Inflammatory stress plays a central role both by promoting endothelial dysfunction and predisposing the vasculature towards a pro-inflammatory state, thus establishing a vicious circuit.40,41 Indeed, chronic inflammation and sustained EC activation contribute to diseases such as atherosclerosis and pulmonary arterial hypertension (PAH), with accumulating evidence suggesting EndMT is a possible key link between inflammation and EC dysfunction.20,42,43
EC heterogeneity: one definition for many cues
Several studies have addressed the remarkable heterogeneity of ECs, highlighting differences in terms of cell structure and organization, which are likely dictated by different embryonic origins and which contribute to EC specialization. This reflects the wide array of functions that ECs perform to maintain cell homeostasis while adapting to site-specific demands.6,24,44 The intrinsic plasticity and adaptation capacity of ECs are paramount in determining cell fate changes in pathologic conditions affecting endothelium normalcy.11,23 In disease, EC heterogeneity appears to be fairly broad, being defined by factors such as changes in the proportions of cellular subpopulations present both in health and disease, their restricted expression only in an experimental group/condition, as well as changes in the EC interactome and morphological/functional properties.7 At the far end of the heterogeneity spectrum, ECs can undergo either transient or permanent cellular fate and functional adaptions, as observed in EndMT where a subset of ECs undergo profound changes.6,7,45 It is therefore reasonable to hypothesize that EndMT-responsive EC subsets may be primed to respond to homeostatic disruptions, either by hindering or advancing endothelial dysfunction. Which are the molecular switches guiding this decision and whether they are conserved across EndMT-associated pathologies or present in context-specific scenarios remain to be elucidated, representing the subject of intense investigation.
Source : https://rb.gy/vtgu41