Inhibition of platelet derived growth factor promotes pericyte loss and angiogenesis in retinopathy of prematurity.

Abstract

Abstract: : Purpose: Emerging evidence indicates that platelet derived growth factor (PDGF) is critical for pericyte viability. We investigated whether inhibition of PDGF receptor tyrosine kinase activity would affect angiogenesis, pericyte viability and vascular endothelial growth factor (VEGF)/VEGFR–2 expression in a model of retinopathy of prematurity (ROP). Methods: ROP was induced in Sprague Dawley rats by exposure to 80% oxygen from postnatal (P) days 0–11 (with 3 hours/day in room air), and then room air from P12–18 (angiogenesis period). Shams were neonatal rats in room air from P0–18. STI571 (Glivec, Gleevec, Novartis Pharma AG, Switzerland), a potent inhibitor of PDGF receptor tyrosine kinase, was administered by intraperitoneal injection from P12–18 at 50 or 100 mg/kg/day. Results: Quantitation of blood vessel profiles (BVPs) in the inner retina revealed BVPs to be increased with ROP and further increased with STI571. Sham rats treated with the highest dose of STI571 also exhibited an increase in BVPs in the inner retina. Electron microscopy revealed that pericytes in the inner retina of both sham and ROP rats appeared normal; however STI571 induced a selective pericyte and vascular smooth muscle degeneration. Quantitation of α–smooth muscle cell actin (pericyte marker) and caspase–3 (apoptotic marker) positive cells in the inner retina confirmed that pericyte apoptosis was enhanced in ROP rats treated with STI571. In all groups, in situ hybridisation demonstrated that VEGF and VEGFR–2 gene expression was located in ganglion cells, the inner nuclear layer and retinal pigment epithelium. ROP was associated with an approximately 2 fold increase in both VEGF and VEGFR–2 gene expression in the inner retina compared to sham rats. STI571 at both doses further increased VEGF and VEGFR–2 mRNA in ROP rats, and in sham rats at 100 mg/kg/day. Conclusion: PDGF is required for pericyte viability and the subsequent prevention of VEGF/VEGFR–2 over–expression and angiogenesis in ROP. These findings may have implications for diabetic retinopathy which features extensive pericyte loss and subsequent angiogenesis.

Keywords: growth factors/growth factor receptors • retina • vascular cells