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(Circulation Research. 2005;96:1282.)
© 2005 American Heart Association, Inc.

Cellular Biology

Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca² Influx

David Jho, Dolly Mehta, Gias Ahmmed, Xiao-Pei Gao, Chinnaswamy Tiruppathi, Michael Broman, Asrar B. Malik

From the Department of Pharmacology and The Center of Lung and Vascular Biology, The University of Illinois, Chicago.

Correspondence to Dr Asrar B. Malik, Department of Pharmacology, University of Illinois at Chicago, 835 S Wolcott Ave (M/C 868), Chicago, IL 60612. E-mail abmalik{at}uic.edu

Angiopoietin-1 (Ang1) exerts a vascular endothelial barrier protective effect by blocking the action of permeability-increasing mediators such as vascular endothelial growth factor (VEGF) through unclear mechanisms. Because VEGF may signal endothelial hyperpermeability through the phospholipase C (PLC)-IP₃ pathway that activates extracellular Ca²⁺ entry via the plasmalemmal store-operated channel transient receptor potential canonical-1 (TRPC1), we addressed the possibility that Ang1 acts by inhibiting this Ca²⁺ entry mechanism in endothelial cells. Studies in endothelial cell monolayers demonstrated that Ang1 inhibited the VEGF-induced Ca²⁺ influx and increase in endothelial permeability in a concentration-dependent manner. Inhibitors of the PLC-IP₃ Ca²⁺ signaling pathway prevented the VEGF-induced Ca²⁺ influx and hyperpermeability similar to the inhibitory effects seen with Ang1. Ang1 had no effect on PLC phosphorylation and IP₃ production, thus its permeability-decreasing effect could not be ascribed to inhibition of PLC activation. However, Ang1 interfered with downstream IP₃-dependent plasmalemmal Ca²⁺ entry without affecting the release of intracellular Ca²⁺ stores. Anti-TRPC1 antibody inhibited the VEGF-induced Ca²⁺ entry and the increased endothelial permeability. TRPC1 overexpression in endothelial cells augmented the VEGF-induced Ca²⁺ entry, and application of Ang1 opposed this effect. In immunoprecipitation studies, Ang1 inhibited the association of IP₃ receptor (IP₃R) and TRPC1, consistent with the coupling hypothesis of Ca²⁺ entry. These results demonstrate that Ang1 blocks the TRPC1-dependent Ca²⁺ influx induced by VEGF by interfering with the interaction of IP₃R with TRPC1, and thereby abrogates the increase in endothelial permeability.

Key Words: endothelial permeability • vascular endothelial growth factor • angiopoietin-1 • Ca²⁺ influx • transient receptor potential channel

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