VEGF-induced relaxation of pulmonary arteries is mediated by endothelial cytochrome P-450 hydroxylase. Am J Physiol Lung Cell Mol Physiol 2006 Sep;291(3):L369-77
Date
05/09/2006Pubmed ID
16679379DOI
10.1152/ajplung.00265.2004Scopus ID
2-s2.0-33748435644 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
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 Ca(2+) in renal artery endothelial cells as observed in bovine pulmonary artery endothelial cells (BPAECs). VEGF-evoked increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) in BPAECs were blunted by treatment with DDMS. Both VEGF (10 nM) and 20-HETE (1-5 microM) 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.
Author List
Jacobs ER, Zhu D, Gruenloh S, Lopez B, Medhora MMESH terms used to index this publication - Major topics in bold
AmidesAnimals
Calcium
Cattle
Cytochrome P-450 Enzyme Inhibitors
Endothelium, Vascular
Hydrolases
Hydroxyeicosatetraenoic Acids
In Vitro Techniques
Muscle Relaxation
Nitric Oxide
Pulmonary Artery
Renal Artery
Sulfones
Vascular Endothelial Growth Factor A