Pericytes and the Pathogenesis of Diabetic Retinopathy
- Hans-Peter Hammes1,
- Jihong Lin1,
- Oliver Renner2,
- Moshe Shani3,
- Andrea Lundqvist4,
- Christer Betsholtz4,
- Michael Brownlee5 and
- Urban Deutsch6
- 1Fifth Medical Clinic, Medical Faculty of the University of Heidelberg, Mannheim, Germany
- 2Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
- 3Institute of Animal Science, the Volcani Center, Bet Dagan, Israel
- 4Department of Medical Biochemistry, Goteborg University, Goteborg, Sweden
- 5Albert Einstein College of Medicine, Bronx, New York, New York
- 6Max-Planck Institute for Vascular Biology, Münster, Germany
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.
Address correspondence and reprint requests to Hans-Peter Hammes, Fifth Medical Clinic, Medical Faculty of the University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany. E-mail:.
Received for publication 23 April 2002 and accepted in revised form 17 July 2002.
AGE, advanced glycation end product; PDGF, platelet-derived growth factor; ROP, retinopathy of prematurity; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.