Fc-saxatilin inhibits VEGF-induced permeability by regulating claudin-5 expression in human brain microvascular endothelial cells

Abstract

The disruption of the blood-brain barrier influences the degree of brain damage and prognosis in cerebral ischemia or other brain diseases accompanied by inflammation. Vascular endothelial growth factor (VEGF) released during brain ischemia or inflammation has been implicated in the breakdown of the blood-brain barrier by increasing endothelial permeability. Saxatilin, a disintegrin-containing RGD motif, has been reported to disaggregate platelets via interactions with platelet integrins and to have a thrombolysis effect. Additionally, the Fc-saxatilin fusion protein reduces vascular leakage in cerebral ischemia in mice. In this study, we show that Fc-saxatilin prevents VEGF-induced permeability in human brain microvascular endothelial cells (HBMECs). The activation of Src and Fak, downstream signaling proteins of VEGF in the induction of endothelial permeability, was inhibited by Fc-saxatilin in HBMECs. The downregulation of a tight junction protein, claudin-5, at the protein and mRNA levels by VEGF was recovered by Fc-saxatilin. Our findings suggest that Fc-saxatilin attenuates VEGF-induced endothelial permeability via the regulation of downstream signaling, and this may contribute to its protective effect against vascular leakage in the ischemic brain.