Pericytes in the disease spotlight

Molecular and functional pericyte studies at single-cell resolution are providing new insights into long-standing questions about pericyte heterogeneity.Pericytes are not identified by a single marker but instead by gene expression signatures that show substantial inter-organ differences.Pericytes orchestrate and precede endothelial cell responses during angiogenesis.Pericyte degeneration and dysfunction, that are triggered by the onset of some diseases, contribute to the progression of those diseases in both vascular and non-vascular contexts.The number of diseases with pericyte dysfunction continues to expand, thereby anticipating a promising future for pericyte-focused therapy. Pericytes are classically defined as mural cells (see Glossary) that envelop the endothelium of small caliber blood vessels, the so-called capillaries. Pericytes are embedded within the same basement membrane as endothelial cells (ECs) and interact closely with them [1.Armulik A. et al.Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm A. et al.Microvascular mural cell organotypic heterogeneity and functional plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. By contrast, vascular smooth muscle cells (vSMCs), the other mural cell type, cover large arteries and veins, and are physically separated from the endothelium by an intimal layer of extracellular matrix (ECM). Of note, lymphatic capillaries lack pericytes under physiological conditions, although collecting lymphatic vessels contain vSMCs [3.Petrova T.V. Koh G.Y. Biological functions of lymphatic vessels.Science. 2020; 369eaax4063Crossref PubMed Scopus (144) Google Scholar]. A fundamental function of mural cells is to regulate the stabilization and function of blood vessels. It is therefore not surprising that pericyte loss and dysfunction were linked to several diseases including cancer and cerebrovascular diseases more than a decade ago [4.Martin J.D. et al.Normalizing function of tumor vessels: progress, opportunities, and challenges.Annu. Rev. Physiol. 2019; 81: 505-534Crossref PubMed Scopus (242) Google Scholar,5.Lendahl U. et al.Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes.EMBO Rep. 2019; 20e48070Crossref PubMed Scopus (71) Google Scholar]. However, pericyte-focused therapies have been poorly explored. Instead, most studies on vascular-directed therapeutic strategies have been on ECs – the central components that build blood vessels. Emerging data are, however, changing the perception of pericytes from mere supporting vascular cells that are recruited at the final stage of vessel formation to essential elements in the early phases of angiogenesis that anticipate and orchestrate EC behavior. In addition, recent research is revealing novel pathological roles for pericytes beyond their implications in the vasculature. Collectively, we believe that these data open exciting avenues for pericyte-focused therapeutic approaches and call for a broader understanding of these cells in disease progression. We provide here a global overview of recent significant advances regarding our understanding of the role of pericytes in different pathobiological scenarios and discuss the field's current paradigms and controversies. First, we address new insights into the functions associated with pericytes during physiological vascular responses. Second, we discuss evidence supporting a role of pericytes in disease, including pericyte cell-autonomous implications beyond the vasculature. For comprehensive details on pericyte biology, function ontology, and specific signaling pathways, we refer the reader to [1.Armulik A. et al.Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm A. et al.Microvascular mural cell organotypic heterogeneity and functional plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,5.Lendahl U. et al.Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes.EMBO Rep. 2019; 20e48070Crossref PubMed Scopus (71) Google Scholar]. Of importance, some of the emerging concepts in pericyte biology described in the following sections have only been studied in one specific tissue. To avoid confusion about the generalizability of pericyte properties, we frame each function by considering the relevant organ of study. Pericytes exhibit significant inter- and intra-tissue molecular differences and exert tissue-specific functions [2.Holm A. et al.Microvascular mural cell organotypic heterogeneity and functional plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. Their molecular, morphological, and functional heterogeneity is inextricably linked to their diverse developmental origins, modes of vessel recruitment, and specific anatomical localization. For example, pericytes of the central nervous system (CNS) microvasculature are firmly and continuously invested around the endothelium to support vascular barrier properties, whereas liver pericytes, commonly referred to as hepatic stellate cells (HSCs), reside in the perisinusoidal space, are loosely and discontinuously associated to ECs, and hold a unique vitamin A storage capacity [2.Holm A. et al.Microvascular mural cell organotypic heterogeneity and functional plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. To meet tissue-specific demands, pericyte distribution and density are variable among organs and vascular beds, with the CNS microvasculature showing the greatest pericyte-to-EC abundance. 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