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Am J Physiol Lung Cell Mol Physiol (May 5, 2006). doi:10.1152/ajplung.00424.2005
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Submitted on October 4, 2005
Accepted on March 29, 2006

Mechanisms of activation of eNOS by 20-hydroxyeicosatetraenoic acid and VEGF in bovine pulmonary artery endothelial cells

Yuenmu Chen1, Meetha M Medhora1, John R Falck2, Kirkwood A Pritchard3, and Elizabeth R. Jacobs1*

1 Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Biochemistry, University Of Texas, Dallas, Texas, United States
3 Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States

* To whom correspondence should be addressed. E-mail: ejacobs{at}mcw.edu.

We have demonstrated that VEGF induced dilation of bovine pulmonary arteries (PAs) is associated with activation of cytochrome P450 family 4 (CYP4) enzymes and endothelial nitric oxide synthase (eNOS). We hypothesized that VEGF and the CYP4 product 20-HETE would trigger common downstream pathways of intracellular signaling to activate eNOS. We treated BPAECs with 20-HETE (1 µM) or VEGF (8.3 nM) and examined 3 molecular events known to activate eNOS: 1) phosphorylation at serine 1179 2) phosphorylation of protein kinase B (AKT) that subsequently phosphorylates eNOS 3) association of eNOS with Hsp90. Both 20-HETE and VEGF increase the phosphorylation of eNOS at serine 1179 and AKT at serine 473. The CYP4 inhibitor DDMS blocks VEGF induced phosphorylation of eNOS. VEGF had no effect on the binding of Hsp90 with eNOS, whereas 20 HETE decreased the association of the protein partners. Inhibition of AKT-PI3 kinase with wortmannin blocks both 20-HETE and VEGF-induced relaxation of PAs, supporting the functional contribution of AKT phosphorylation to the vasoactive actions of both agents. Treatment with radicicol had no effect on 20-HETE-induced relaxation of pulmonary arteries, consistent with an absence of effect on association of Hsp90 to eNOS, whereas radicicol partially blocked VEGF evoked relaxations, possibly secondary to effects on endpoints other than Hsp90 association with eNOS. In conclusion VEGF and 20-HETE share eNOS activation pathways including phosphorylation of serine 1179 and phosphorylation of AKT. Unlike aortic endothelial cells, eNOS activation in BPAECs by either VEGF or 20-HETE does not appear to require increased association of Hsp90.




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