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1 Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
2 Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
3 Pathology, Vanderbilt University Medical Center, Nashville, TN, USA; Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: barbara.meyrick{at}vanderbilt.edu.
This study examines the notion that Hsp90 binding to eNOS, nitric oxide (NO) and PI3K-Akt regulate angiopoietin-1 (Ang-1) induced angiogenesis in porcine coronary artery endothelial cells (PCAEC). Exposure to Ang-1 (250 ng/ml) for periods up to two hours resulted in a time-dependent increase in eNOS phosphorylation at Ser1177 that occurred by five minutes and peaked at 60 minutes. 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 pretreatment of cells with either 1µg/ml geldanamycin (a specific inhibitor of Hsp90) or 500nM wortmannin (a specific PI3 kinase 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 NOS by L-NAME (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.
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