Activin A Limits VEGF-Induced Permeability via VE-PTP

Abstract

The clinical success of neutralizing vascular endothelial growth factor (VEGF) has unequivocally identified VEGF as a driver of retinal edema that underlies a variety of blinding conditions. VEGF is not the only input that is received and integrated by the endothelium. For instance, the permeability of blood vessels is also regulated by the large and ubiquitously expressed transforming growth factor beta (TGF-β) family. In this project, we tested the hypothesis that members of the TGF-β family influence the VEGF-mediated control of the endothelial cell barrier. To this end, we compared the effect of bone morphogenetic protein-9 (BMP-9), TGF-β1, and activin A on the VEGF-driven permeability of primary human retinal endothelial cells. While BMP-9 and TGF-β1 had no effect on VEGF-induced permeability, activin A limited the extent to which VEGF relaxed the barrier. This activin A effect was associated with the reduced activation of VEGFR2 and its downstream effectors and an increased expression of vascular endothelial tyrosine phosphatase (VE-PTP). Attenuating the expression or activity of VE-PTP overcame the effect of activin A. Taken together, these observations indicate that the TGF-β superfamily governed VEGF-mediated responsiveness in a ligand-specific manner. Furthermore, activin A suppressed the responsiveness of cells to VEGF, and the underlying mechanism involved the VE-PTP-mediated dephosphorylation of VEGFR2.