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J Appl Physiol 96: 612-620, 2004. First published October 10, 2003; doi:10.1152/japplphysiol.00728.2003
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HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium

Jian-xiong Chen,1 Mayme Lee Lawrence,1 Gary Cunningham,2 Brian W. Christman,2 and Barbara Meyrick1

Departments of 1Pathology and 2Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2650

Submitted 15 July 2003 ; accepted in final form 3 October 2003

This study examines the notion that heat shock protein (HSP) 90 binding to nitric oxide (NO), endothelial NO synthase (eNOS), and PI3K-Akt regulate angiopoietin (Ang)-1-induced angiogenesis in porcine coronary artery endothelial cells (PCAEC). Exposure to Ang-1 (250 ng/ml) for periods up to 2 h resulted in a time-dependent increase in eNOS phosphorylation at Ser 1177 that occurred by 5 min and peaked at 60 min. This was accompanied by a gradual increase in NO release. Ang-1 also led to stimulation of HSP90 binding to eNOS and a significant increase in Akt phosphorylation. Thirty minutes of pretreatment of cells with either 1 µg/ml geldanamycin (a specific inhibitor of HSP90) or 500 nM wortmannin [a specific phosphatidylinositol 3 (PI3)-kinase (PI3K) inhibitor] significantly attenuated Ang-1-stimulated eNOS phosphorylation and NO production. Exposure to Ang-1 caused an increase in endothelial cell migration, tube formation, and sprouting from PCAEC spheroids, and pharmacological blockage of HSP90 function or inhibition of PI3K-Akt pathway completely abolished these effects. Inhibition of nitric oxide synthase by NG-nitro-L-arginine methyl ester (2.5 mM) also resulted in a significant decrease in Ang-1-induced angiogenesis. We conclude that stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to Ang-1-induced eNOS phosphorylation, NO production, and angiogenesis in PCAEC.

phosphorylated endothelial nitric oxide synthase; Tie-2 receptor; neovascularization; signal transduction


Address for reprint requests and other correspondence: B. Meyrick, Center for Lung Research, Vanderbilt Univ. Medical Center, MCN T-1217, Nashville, TN 37232-2650 (E-mail: barbara.meyrick{at}vanderbilt.edu).




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