Brain pericyte biology: from physiopathological mechanisms to potential therapeutic applications in ischemic stroke

Abstract

Pericytes play an indispensable role in various organs and biological processes, such as promoting angiogenesis, regulating microvascular blood flow, and participating in immune responses. Therefore, in this review, we will first introduce the discovery and development of pericytes, identification methods and functional characteristics, then focus on brain pericytes, on the one hand, to summarize the functions of brain pericytes under physiological conditions, mainly discussing from the aspects of stem cell characteristics, contractile characteristics and paracrine characteristics; on the other hand, to summarize the role of brain pericytes under pathological conditions, mainly taking ischemic stroke as an example. Finally, we will discuss and analyze the application and development of pericytes as therapeutic targets, providing the research basis and direction for future microvascular diseases, especially ischemic stroke treatment.

Keywords: brain pericytes; contractile characteristics; ischemic stroke; paracrine characteristics; stem cell characteristics.

Figure 1

Three major properties of pericytes. (1) stem cell properties: Under the induction of bFGF and other factors, pericytes could differentiate into glial cells, neurons, fibroblasts, smooth muscle cells and fat cells; (2) contractile properties: pericytes in the spinal cord, retina, heart, and brain have contractile abilities; (3) paracrine properties: pericytes can communicate and interact with endothelial cells, neurons, astrocytes and white blood cells to achieve more biological functions.

Figure 2

Factors that impact the contractile characteristics of cerebrovascular pericytes. (1) Ca²⁺: the increase in the rate of glycogenolysis decomposition and ATP production leads to the increase in the concentration of intracellular calcium ion and subsequent pericyte contraction; (2) reactive oxygen species: hypoxia, hyperglycemia, hydrogen peroxide, and radiation can result in the increase in intracellular reactive oxygen species, through which the concentration of calcium ion is increased and subsequently pericytes contract; (3) regulatory factors: endothelin-1 induces contraction by acting on its type-A receptor, while CNP can inhibit endothelin-1-induced contraction through the GC-B/cGMP signaling pathway; (4) membrane proteins: inhibition of α-smooth muscle actin expression could prevent contraction, GPR39 knockout results in pericyte contraction; (5) other mediators: SARS virus infection induces pericyte contraction by interacting with cell surface membrane proteins. Abbreviated specification: A2AR-A2A receptors; GP: glycogen phosphorylase; GDE: glycogen debranching enzyme; Glc-1-p: glucose 1- (dihydrogen phosphate); Glc-6-p: glucose 6- (dihydrogen phosphate); Glc: Glucose; ROS: reactive oxygen species; CNP: C-type natriuretic peptide; NPR-B(GC-B): natriuretic peptide receptor-B (Guanylate cyclase B); EDNT: endothelin-1; EDNRA: endothelin Receptor Type A; GTP: Guanosine triphosphate; cGMP: cyclic guanosine monophosphate; cGKI: cGMP-dependent protein kinase I; PDE3A: Phosphodiesterase 3A; cAMP: Cyclic Adenosine Monophosphate; GPR39: G protein-coupled receptor 39; α-SMA: Alpha-smooth muscle actin; mTOR: Mammalian target of rapamycin; ACE2: Angiotensin-Converting Enzyme 2.

Figure 3

Paracrine characteristics of cerebrovascular pericytes. (1) participation in angiogenesis and maturation: this biological process is mainly due to the communication between pericytes and endothelial cells. VEGF/VEGFR1 pathway is mainly involved in vascular budding, PDGF-BB-PDGFR-β pathway is mainly involved in vascular stability, and TGF-β pathway is mainly involved in vascular maturation; (2) maintenance of the blood–brain barrier permeability: Ang/Tie2 and MFSD2A pathways play a crucial role in regulating the vascular permeability, Sonic Hedgehog from astrocytes can also stabilize the permeability of the blood–brain barrier by acting on endothelial cells; (3) regulation of capillary blood flow: prostaglandin E2 released by astrocytes can actively relax pericytes, but this process requires the release of NO to inhibit the synthesis of 20-HETE which constricts blood vessels; (4) regulation of neuroinflammation: this process mainly involves the communication between endothelial cells, pericytes and astrocytes. Pericytes promote the activation of astrocytes and promote the expression of pro-inflammatory factors in endothelial cells by secreting IL-1β and TNF-α, and pericytes also can release CXCL1 on white blood cells. Abbreviated specification: VEGFA-vascular endothelial growth factor A; VEGFR1: Vascular endothelial growth factor receptor 1; VEGFR2: Vascular endothelial growth factor receptor 2; VEGF-A165:vascular endothelial growth factor A165; PDGFRβ: Platelet-derived growth factor receptor-β; PDGF-BB: Platelet-Derived Growth Factor BB; TGFβ: Transforming growth factor beta; TGFβ-R2: Transforming growth factor beta, type II receptor; Ang1: angiopoietin-1; Tie2: TEK receptor tyrosine kinase; MFSD2A: major facilitator superfamily domain-containing protein 2a; 20-HETE: 20-hydroxy Arachidonic Acid; IL-1β: interleukin-1β; IL-1: interleukin-1; IL-6: interleukin-6; IL-12: interleukin-12; TNFα: tumor necrosis factor α; CXCL1: Recombinant Human C-X-C Motif Chemokine 1; MCP-1: Monocyte Chemotactic Protein 1.