Fig. 5

The molecular interplays between pericytes and endothelial cells. A In normal retina, the survival of endothelial cells is supported by VEGF-A/VEGFR-1. The microvascular stabilization is maintained together by endothelial cells-derived PDGF-B, which recruits the coverage of the pericytes through binding to PDGFRβ on pericytes. The pericytes secreted Ang-1, promoting the vascular stabilization via binding Tie2 on the endothelial cells, and TGF-β, promoting pericyte differentiation through binding to TGF-β receptors on pericytes. B In DR, hypoxia and hyperglycemia increased the expressions of various cytokines and growth factors, such as VEGF, PlGF, Ang-2, and VE-PTP. VEGF and PlGF can activate the endothelial cells, break down the iBRB, and promote the inflammation through binding to VEGFR-1/2 on the endothelial cells and the inflammatory cells. PlGF induces the pericyte dropout via binding to VEGFR-1 on pericytes. Ang-2 results in the pericyte and astrocyte loss or dropout through binding to integrin receptors on their cell surface, further sensitizing the endothelial cells to VEGF and PlGF. Ang-2 destabilizes the endothelial cells through binding to Tie2 or integrin, leading to the vascular leakage, inflammation, and even neovascularization. VE-PTP dephosphorylates Tie2 and inactivates Tie2, further causing the microvascular destabilization. Besides, other cytokines, growth factors and inflammatory factors, such as TNFα, IL-1β, IL-6, ICAM-1, VCAM-1, MCP-1, BMP2, BMP4, sSema4D, and S1P, are also involved in the microvascular destabilization. These molecules, working synergistically, form the complex molecular networks and result in the iBRB breakdown, retinal vascular hyperpermeability, inflammation, and neovascularization, aggravating the disease progression of DR. The ligands (e.g., TGF-β, PDGF-B, and Ang-2) and the corresponding receptors (e.g., TGF-β receptor, PDGFRβ, and Tie2) are grouped together in Figure A and B. The arrows from the cells indicate the growth factors or cytokines produced by the cells; while the arrows towards the cells indicate the growth factors or cytokines exert their effects through binding to their corresponding receptors on the target cells. For example, PDGF-B is produced by the endothelial cells, which recruits pericytes through binding to PDGFRβ on pericytes. Ang-1: angiopoietin 1; Ang-2: angiopoietin 2; BMP2: bone morphogenetic protein 2; BMP4: bone morphogenetic protein 4; DR: diabetic retinopathy; ICAM-1: intercellular adhesion molecule-1; IL-1β: interleukin-1β; IL-6: interleukin-6; MCP-1: monocyte chemotactic protein 1; PDGF-B: platelet-derived growth factor; PDGFRβ: platelet-derived growth factor receptor β; PlGF: placental growth factor; S1P: sphingosine-1-phosphate; sSema4D: soluble semaphorin 4D; Tie2: tyrosine kinase with immunoglobulin-like and the epidermal growth factor-like domains 2; TNFα: tumor necrosis factor α; VCAM-1: vascular cellular adhesion molecule-1; VEGF-A: vascular endothelial growth factor A; VEGFR-1/2: vascular endothelial growth factor-1/2; VE-PTP: vascular endothelial protein tyrosine phosphatase. This figure was created with BioRender.com