Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca ² Influx

Abstract

Abstract-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)-IP 3 pathway that activates extracellular Ca 2ϩ entry via the plasmalemmal store-operated channel transient receptor potential canonical-1 (TRPC1), we addressed the possibility that Ang1 acts by inhibiting this Ca 2ϩ entry mechanism in endothelial cells. Studies in endothelial cell monolayers demonstrated that Ang1 inhibited the VEGF-induced Ca 2ϩ influx and increase in endothelial permeability in a concentration-dependent manner. Inhibitors of the PLC-IP 3 Ca 2ϩ signaling pathway prevented the VEGF-induced Ca 2ϩ influx and hyperpermeability similar to the inhibitory effects seen with Ang1. Ang1 had no effect on PLC phosphorylation and IP 3 production, thus its permeability-decreasing effect could not be ascribed to inhibition of PLC activation. However, Ang1 interfered with downstream IP 3 -dependent plasmalemmal Ca 2ϩ entry without affecting the release of intracellular Ca 2ϩ stores. Anti-TRPC1 antibody inhibited the VEGF-induced Ca 2ϩ entry and the increased endothelial permeability. TRPC1 overexpression in endothelial cells augmented the VEGF-induced Ca

New Insight on the Role of Transient Receptor Potential (TRP) Channels in Driven Gliomagenesis Pathways

“…TRPC1 overexpression in endothelial cells augmented the VEGF-induced Ca(2+) entry, and application of Ang1 opposed this effect. Consistent with the coupling hypothesis of Ca(2+) entry, Ang1 by inhibiting the association of IP3 receptor (IP3R) and TRPC1, abrogates the increase in endothelial permeability (Jho et al, 2005). Although the previously reported study has been focused on Ang1 regulation of TRPC1 activation, we cannot rule out the involvement of other relevant TRPC channels.…”

The Complex Role of Angiopoietin-2 in the Angiopoietin-Tie Signaling Pathway

“…Decreased expression of adhesion proteins including ICAM-1, VCAM-1, and, E-selectin has been attributed to activation of the PI3-kinase/AKT pathway (Kim et al 2001). With respect to permeability, several reports suggest that Ang1 works by inhibiting calcium influx and/or activation of the small GTPase Rho (Li et al 2004;Jho et al 2005). Both calcium flux and Rho are believed to promote permeability through effects on the actin cytoskeleton.…”

Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca 2+ channel to maintain endothelial integrity

“…The TRPC family consists of seven isoforms, each of which shows specific cellular distribution and functions (13,14). TRPC-1, TRPC-3, TRPC-4, and TRPC-6 are expressed in the ECs, and these subtypes are closely involved in various vascular functions: TRPC-1 in VEGF-mediated Ca 2+ entry (13)(14)(15), TRPC-4 in hypoxia-induced vascular remodeling, and TRPC-3 and TRPC-4 in oxidative stress-induced responses (16). The association with Klotho protein has not yet been studied.…”