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L.H. Smith, S.–C. Shih, M. Ju, N. Liu, J.–R. Mo, J. Ney; Transforming growth factor–ß1 induction of vascular endothelial growth factor receptor–1: Mechanism of pericyte–induced vascular survival in vivo . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3523.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Oxygen–induced loss of VEGF precipitates the degeneration of vessels in retinopathy of prematurity (ROP). Vessel survival depends on VEGF activation of VEGFR–1. In diabetic retinopathy, pericyte dropout is associated with vessel loss. In neonates, vessels without pericytes are more susceptible to oxygen–induced vessel degeneration. These results suggest that pericyte support of vessel survival appears related to VEGF–induced survival. We examined in the mouse model of ROP the hypothesis that one mechanism of pericyte protection is through TGF–ß induction of VEGFR–1 in vascular endothelial cells. Methods: We examined TGF–ß1 induction of VEGFR–1 mRNA expression in bovine retinal endothelial cells. In mice we examined the effect of systemic TGF–ß1 on a) retinal VEGFR–1 mRNA expression with real time RT–PCR and b) oxygen–induced vessel loss using FITC perfused whole mounted retina. Retinal pericyte (NG2, αSMA) and endothelial cell (GSI lectin) and TGF–ß1 and VEGFR–1 distributions were visualized with immunohistochemical and ISH localization. In mice we also examined the effect of systemic TGF–ß1 plus PlGF–1 (a specific ligand of VEGR–1) on oxygen–induced vessel loss using FITC perfused whole mounted retina. Results: TGF–ß1 expressing pericytes are specifically found on vessels resistant to oxygen–induced loss. TGF–ß1 potently induces VEGFR–1 expression in endothelial cells and in retina, and prevents oxygen–induced vessel loss in vivo. TGF–ß1 plus the VEGFR–1 specific ligand PlGF–1 further increases protection from hyperoxia–induced degeneration. In retinal whole mounts, TGF–ß1 protein coincides with pericytes expressing αSMA and with vessels resistant to oxygen. Conclusions: TGF–ß1 induction of VEGFR–1 in endothelial cells explains pericyte protection of vessels and the selective vulnerability of neonatal vessels to oxygen. These results implicate induction and activation of VEGFR–1 as critical targets to prevent vessel loss.
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