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Diabetes 52:2959-2968, 2003
© 2003 by the American Diabetes Association, Inc.

Activation of Vascular Endothelial Growth Factor Receptor-1 Sustains Angiogenesis and Bcl-2 Expression Via the Phosphatidylinositol 3-Kinase Pathway in Endothelial Cells

Jun Cai1, Shakil Ahmad2, Wen G. Jiang3, Jianhua Huang4, Christopher D. Kontos4, Mike Boulton1, and Asif Ahmed2

1 Department of Optometry and Vision Sciences, Cardiff University, Cardiff, U.K
2 Department of Reproductive and Vascular Biology, Medical School, University of Birmingham, Birmingham, U.K
3 Department of Surgery, University of Wales College of Medicine, Cardiff, U.K
4 Department of Medicine, Duke University Medical Center, Durham, North Carolina

Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however, how PlGF, which is elevated in proliferative diabetic retinopathy and is a VEGF homolog that binds only to VEGF receptor (VEGFR)-1, promotes pathological angiogenesis. When primary microvascular endothelial cells were grown on collagen gels, PlGF-containing ligands upregulated Bcl-2 expression and stimulated the formation of capillary-like tube networks that were retained for up to 14 days in culture. The inhibition of VEGFR-1 results in a dramatic decrease in the number of capillary connections, indicating that VEGFR-1 ligands promote branching angiogenesis. In contrast, VEGF-induced tube formations and Bcl-2 expression were significantly decreased at the end of this period. Flow cytometry analysis of annexin-V/propidium iodide–stained cells revealed that PlGF and PlGF/VEGF heterodimer inhibited apoptosis in serum-deprived endothelial cells. These two growth factors stimulated a survival signaling pathway phosphatidylinositol 3-kinase (PI3K), as identified by increased Akt phosphorylation and because blocking PI3K signalling by adenovirus-mediated overexpression of wild-type phosphatase and tensin homolog on chromosome 10 (PTEN) disrupted angiogenesis and decreased Bcl-2 expression by PlGF and PlGF/VEGF heterodimer, whereas a dominant-negative PTEN mutant enhanced endothelial sprout formation and Bcl-2 expression. Together, these findings indicate that PlGF-containing ligands contribute to pathological angiogenesis by prolonging cell survival signals and maintaining vascular networks.

Address correspondence and reprint requests to Professor Asif Ahmed, Department of Reproductive and Vascular Biology, University of Birmingham, the Medical School, Edgbaston, Birmingham B15 2TG, U.K. E-mail: a.s.ahmed{at}bham.ac.uk


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