Pericytes and the Pathogenesis of Diabetic Retinopathy

Abstract

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B ؉/؊ mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B ؉/؊ mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B ؉/؊ mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B ؉/؊ mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B ؉/؊ mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo. Diabetes 51:3107-3112, 2002

Transforming growth factor β1 induction of vascular endothelial growth factor receptor 1: Mechanism of pericyte-induced vascular survival in vivo

“…In neonatal PDGF Ϫ/ϩ mice (with decreased pericyte number) exposed to hyperoxia, proliferative retinopathy is increased, suggesting that further pericyte loss increases susceptibility to oxygen-induced vasoobliteration leading to increased proliferative disease (10). Interestingly, in the neonate, not all pericytes (as defined by NG2) express TGF-␤1.…”

“…In mice with pericyte deficiency (PDGF Ϫ/ϩ ) made diabetic, vessel loss is increased further (10). Our studies have not specifically addressed the role of TGF-␤1 and VEGFR-1 in diabetic animals.…”

“…In mice lacking plateletderived growth factor (PDGF)-B in endothelial cells, pericyte recruitment is compromised and vessel loss is similar to that of early DR (11). In PDGF Ϫ/ϩ mice with pericyte deficit, vessel loss is increased further in diabetic animals (10). Pericytes are also important in the developing retina.…”

“…Pericytes are also important in the developing retina. In neonates, vessels without pericytes are more susceptible to oxygen-induced vessel degeneration (9,10). These results suggest that pericyte support of vessel survival appears to be related to VEGF-induced survival, and we sought to identify a molecular mechanism that rationalizes this cooperativity.…”

“…Blood vessels in adults are much more resistant to oxygeninduced loss (7,8) but degenerate without pericyte protection (9,10). Animal models have better defined the association between pericyte loss and vessel loss in diabetes.…”