HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/L369    most recent 00265.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Jacobs, E. R. Articles by Medhora, M. Search for Related Content PubMed PubMed Citation Articles by Jacobs, E. R. Articles by Medhora, M.

VEGF-induced relaxation of pulmonary arteries is mediated by endothelial cytochrome P-450 hydroxylase

¹Cardiovascular Center, Pulmonary and Critical Care Division, Department of Medicine and ²Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 13 July 2004 ; accepted in final form 29 March 2006

The cytochrome P-450 metabolite 20-HETE induces calcium-, endothelial-, and nitric oxide (NO)-dependent relaxation of bovine pulmonary arteries (PA). VEGF is an NO-dependent dilator of systemic arteries and plays a key role in maintaining the integrity of the pulmonary vasculature. We tested the effect of VEGF on PA diameter and tone and the contribution of cytochrome P-450 family 4 (CYP4) to vasoactive effects of VEGF. Bovine PA rings (1 mm in diameter) relaxed with VEGF (0.1–10 nM) in an endothelial- and eNOS-dependent manner. This response was blunted by pretreatment with the CYP4 inhibitor dibromododecynyl methyl sulfonamide (DDMS) as well as a mechanistically different CYP4 inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine. PAs also increased in diameter by 6–12% in the presence of VEGF (10 nM), and this increase was attenuated by DDMS. In contrast to that shown in PAs, 20-HETE constricted bovine renal arteries and did not increase intracellular Ca²⁺ in renal artery endothelial cells as observed in bovine pulmonary artery endothelial cells (BPAECs). VEGF-evoked increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in BPAECs were blunted by treatment with DDMS. Both VEGF (10 nM) and 20-HETE (1–5 µM) stimulated NO release from cultured BPAECs, and once again VEGF-induced increases were attenuated by pretreating the cells with DDMS. We conclude that CYP4/20-HETE contributes to VEGF-stimulated NO release and vasodilation in bovine PAs. Given the unique expression of 20-HETE-forming CYP4 in BPAECs vs. systemic arterial endothelial cells, CYP4 may be an important mediator of endothelial-dependent vasoreactivity in PAs.

20-HETE; nitric oxide signaling; vasoreactivity; lung

This article has been cited by other articles:

				M. Medhora, Y. Chen, S. Gruenloh, D. Harland, S. Bodiga, J. Zielonka, D. Gebremedhin, Y. Gao, J. R. Falck, S. Anjaiah, et al. 20-HETE increases superoxide production and activates NAPDH oxidase in pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L902 - L911. [Abstract] [Full Text] [PDF]

				U. R. Michaelis, N. Xia, E. Barbosa-Sicard, J. R. Falck, and I. Fleming Role of Cytochrome P450 2C Epoxygenases in Hypoxia-Induced Cell Migration and Angiogenesis in Retinal Endothelial Cells Invest. Ophthalmol. Vis. Sci., March 1, 2008; 49(3): 1242 - 1247. [Abstract] [Full Text] [PDF]

				C. Morin, C. Guibert, M. Sirois, V. Echave, M. M. Gomes, and E. Rousseau Effects of {omega}-hydroxylase product on distal human pulmonary arteries Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1435 - H1443. [Abstract] [Full Text] [PDF]

				J. Cheng, J.-S. Ou, H. Singh, J. R. Falck, D. Narsimhaswamy, K. A. Pritchard Jr., and M. L. Schwartzman 20-Hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1018 - H1026. [Abstract] [Full Text] [PDF]

				T. Ishizuka, J. Cheng, H. Singh, M. D. Vitto, V. L. Manthati, J. R. Falck, and M. Laniado-Schwartzman 20-Hydroxyeicosatetraenoic Acid Stimulates Nuclear Factor-{kappa}B Activation and the Production of Inflammatory Cytokines in Human Endothelial Cells J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 103 - 110. [Abstract] [Full Text] [PDF]

				H. Singh, J. Cheng, H. Deng, R. Kemp, T. Ishizuka, A. Nasjletti, and M. L. Schwartzman Vascular Cytochrome P450 4A Expression and 20-Hydroxyeicosatetraenoic Acid Synthesis Contribute to Endothelial Dysfunction in Androgen-Induced Hypertension Hypertension, July 1, 2007; 50(1): 123 - 129. [Abstract] [Full Text] [PDF]

				Y. Chen, M. Medhora, J. R. Falck, K. A. Pritchard Jr, and E. R. Jacobs Mechanisms of activation of eNOS by 20-HETE and VEGF in bovine pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L378 - L385. [Abstract] [Full Text] [PDF]