Activin A Prevents Hyperresponsiveness to Vascular Endothelial Growth Factor in Pathologic Blood Vessels by Perturbing the Trafficking of Activated Vascular Endothelial Growth Factor Receptor 2.

Although quality-of-life compromising afflictions, such as diabetic retinopathy (DR), are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor-β superfamily, attenuated VEGF-induced vascular endothelial-cadherin disorganization, pore formation, and permeability of primary human retinal endothelial cells. Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced the expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally localized protein tyrosine phosphatase (PTP1b), whereas protein tyrosine phosphatases present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 at 30 minutes and longer post-stimulation time points. Together, these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGF receptor 2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathologic blood vessels from patients who developed end-stage proliferative DR. This defect rendered human retinal endothelial cell hyperresponsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of proliferative DR in patients.