Abstract 14736: Aria Regulates Ischemia-Induced Angiogenesis and Vasculogenesis Through Modulating the Pi3k/akt/enos Signaling Pathway
Endothelial cells (ECs) and circulating endothelial precursor cells (EPCs) play a central role in the neovessel formation. We previously reported an identification of ARIA that is highly expressed in ECs. Here we show that ARIA regulates PI3K-Akt signaling in both ECs and EPCs, and consequently control the ischemia-induced neovascularization by utilizing ARIA-knockout mice. ECs isolated from ARIA-KO mice demonstrated significantly enhanced migration and tube-formation, and reduced apoptosis as compared with ECs from wild-type mice. We found human late growth EPCs derived from peripheral blood and cord blood abundantly expressed ARIA. Knockdown of ARIA in human late-EPCs substantially accelerated migration and tube-formation, and reduced apoptosis. Neovasculariozation in response to critical hind limb ischemia was significantly enhanced in ARIA-KO mice. Bone marrow (BM) from GFP mice or ARIA-KO/GFP mice was transplanted into wild-type or ARIA-KO mice to generate BM-chimeric mice. BM-chimeric mice with deletion of ARIA specifically in BM or with systemic deletion of ARIA except BM also showed accelerated neovascularization as compared with wild-type mice, indicating the contribution of both ECs and EPCs in enhanced neovessel formation in ARIA-KO mice. Mice transplanted with ARIA-KO/GFP bone marrow demonstrated more GFP/Isolectin-double positive cells in ischemic muscle, suggesting the enhanced vasculogenesis by ARIA-deletion. Gene silencing of ARIA in ECs and EPCs significantly enhanced PI3K/Akt/eNOS signaling induced by VEGF and SDF1α, respectively. Consistently, inhibition of PI3K or eNOS canceled the pro-angiogenic effect of ARIA-silencing in vitro. Furthermore, eNOS inhibition completely abolished the accelerated ischemia-induced neovascularization in ARIA-KO mice in vivo. In conclusion, ARIA is a novel factor modulating PI3K/Akt/eNOS signaling in ECs and EPCs to control neovascularization, and therefore ARIA is an attractive therapeutic target for the treatment of ischemic diseases.
- © 2010 by American Heart Association, Inc.