Recruitment and retention: factors that affect pericyte migration

Abstract

Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed.

Fig. 1

Factors involved in pericyte recruitment and retention during angiogenesis. Angiogenesis requires pericyte–endothelial cell (EC) dissociation, pericyte migration and proliferation. Pericyte mobilization is driven by several factors (PDGF, Ang1, ALK1, S1P, EGF, and Sema3A) and is negatively regulated by others (TGFβ, Ang2, ALK5). The mobilized pericyte is recruited to a nascent vessel through the activity of factors such as SPARC, MMP9, and Sema3A, which results in vessel stabilization

Fig. 2

Modulation of pericyte recruitment at the pericyte-EC interface. Pericyte recruitment to vascular endothelial cells (ECs) is controlled by a complex interplay between multiple signaling pathways. The schematic illustrates some of the better understood signaling cascades that affect pericyte recruitment. PDGF and EGF are released by ECs and bind to PDGFR-β and EGFR (respectively) on pericytes, stimulating pericyte migration and proliferation. S1P binds to EDG-1 expressed by pericytes and ECs, promoting pericyte migration. The Ang1/Tie2 complex enhances pericyte–EC interaction and induces the expression and release of EGF. Ang2 released by ECs binds to Tie2 on ECs and promotes pericyte-EC dissociation. TGFβ binds to TGFβR2, leading to the activation of ALK1 or ALK5. ALK1 activation stimulates pericyte recruitment while ALK5 activation results in cellular quiescence. Sema3A is released by ECs and forms a complex with Nrp1 and Plexin. This promotes enhanced EC migration and vessel remodeling. MMP9 and SPARC drive ECM remodeling, which facilitates growth factor activation and stimulates pericyte recruitment. SPARC, produced by ECs and pericytes, limits the activation of TGFβ and interferes with the ligation of PDGFR and EFGR to their respective ligands