Fig. 6

The comprehensive schematic diagram showing multiple factors are involved in the microvascular destabilization. The chronic hyperglycemia activates multiple biochemical pathways, including the polyol pathway, HBP, PKC pathway, increased AGEs formation, activation of RAAS, and etc. These activated biochemical pathways cause oxidative stress, low-grade inflammation, as well as activation of PARP in the retina. Multiple factors altered the noncellular components (extracellular matrix) of the retinal vascular unit, resulting in the loss of endothelial glycocalyx and thickening of vascular basement membrane. These factors can also alter the cell–cell contacts, including endothelial-endothelial contact, pericyte-endothelial interaction, Müller glia-vascular cells interaction, astrocyte-vascular cells interaction, and microglia-vascular cells interaction. Multiple pathways, including but not limited to VEGF/VEGFR pathways, Ang pathways and VE-PTP, PDGF-B/PDGFRβ pathway, TGF-β family, PKC family, Sema4D/PlexinB1 pathway, S1P signaling pathway, and Ephrin-B2, interact in networks and work synergistically, resulting in microvascular destabilization. The altered extracellular matrix and cell–cell contacts of the vascular unit as well as the increased multiple cytokines and grow factors together compromise the integrity and the function of the vascular unit, resulting in the breakdown of iBRB and the dysfunction of iNVU, further leading to vascular leakage, endothelial dysfunction, pericyte dropout, and even neovascularization in DR. AGEs: advanced glycation end-products; Akt: protein kinase B; Ang-1/2: angiopoietin 1/2; BMP2: bone morphogenetic protein 2; BMP4: bone morphogenetic protein 4; Cx43: connexin 43; DME: diabetic macular edema; DR: diabetic retinopathy; GJIC: gap junction intercellular communication; HBP: hexosamine biosynthetic pathway; iBRB: inner blood-retinal barrier; ICAM-1: intercellular adhesion molecule-1; IL-1β: interleukin-1β; IL-6: interleukin-6; iNVU: inner neurovascular unit; IRMA: intraretinal microvascular abnormalities; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemotactic protein 1; MMPs: matrix metalloproteinases; NPDR: non-proliferative diabetic retinopathy; PARP: Poly(ADP-ribose) polymerase; PDGF-B: platelet-derived growth factor; PDGFRβ: platelet-derived growth factor receptor β; PDR: proliferative diabetic retinopathy; PI3K: phosphoinositide 3-kinase; PlGF: placental growth factor; RAAS: renin–angiotensin–aldosterone system; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; Sema4D: semaphorin 4D; SphK: sphingosine kinase; Tie1/2: tyrosine kinase with immunoglobulin-like and the epidermal growth factor-like domains 1/2; 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; ZO-1: zonula occludens-1