Faculty Collaboration Database

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

05/09/2006

Pubmed ID

16679379

DOI

10.1152/ajplung.00265.2004

Scopus ID

2-s2.0-33748435644 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

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 M

Authors

Elizabeth R. Jacobs MD Emeritus Professor in the Medicine department at Medical College of Wisconsin
Meetha Medhora Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amides
Animals
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