RANKL regulates endothelial cell survival through the phosphatidylinositol 3 -kinase/Akt signal transduction pathway

The maintenance of endothelial integrity is important for prevention of vascular diseases. Several growth factors, such as bFGF and angiopoietin-1, have been shown to suppress endothelial cell apoptosis and thus help to maintain endothelial integrity. Several studies suggested that receptor activator of NF-kappaB (RANK) and its ligand (RANKL) could be involved in endothelial physiology. Using immunofluorescence and reverse transcriptase-polymerse chain reaction, we found that RANK was expressed by endothelial cells, and RANKL was expressed by arterial smooth muscle cells. Furthermore, RANKL suppressed apoptosis of primary cultured endothelial cells. The RANKL-induced survival appeared to be dependent on PI 3'-kinase activity, because wortmannin and LY294002, PI 3'-kinase-specific inhibitors, blocked the RANKL-induced survival effect. RANKL elicited the phosphorylation of the serine-threonine kinase Akt at Ser473 in a PI 3'-kinase-dependent manner. The expression of a dominant-negative form of Akt or pretreatment of Akt-specific inhibitor in endothelial cells reversed the RANKL-induced survival effect. Tumor necrosis factor-alpha, which causes endothelial cell apoptosis, induced endothelial cells to express osteoprotegerin, a decoy receptor that inhibits RANK-RANKL signaling. These findings indicate that RANK, in response to the paracrine stimulus of RANKL, may play an important role in maintaining endothelial cell integrity through the PI 3'-kinase/Akt signal transduction pathway.
Publisher
Federation Amer Soc Exp Biol
Issue Date
2003-09
Language
ENG
Keywords

NF-KAPPA-B; OSTEOPROTEGERIN-LIGAND; OSTEOCLAST DIFFERENTIATION; RECEPTOR ACTIVATOR; INDUCED APOPTOSIS; EXPRESSION; ANGIOGENESIS; BONE; AKT; CALCIFICATION

Citation

FASEB JOURNAL, v.17, pp.2163 -

ISSN
0892-6638
DOI
10.1096/fj.03-0215fje
URI
http://hdl.handle.net/10203/82428
Appears in Collection
MSE-Journal Papers(저널논문)
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