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1 Pulmonary and Critical Care Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: ejacobs{at}mcw.edu.
The cytochrome P450 (CYP) metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) induces calcium-, endothelial- and nitric oxide (NO)-dependent relaxation of bovine pulmonary arteries (PA). Vascular endothelial growth factor (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 pulmonary artery (PA) diameter and tone and the contribution of CYP4 to vasoactive effects of VEGF. Bovine PA rings (1mm in diameter) relaxed to VEGF (0.1-10 nM) in an endothelial- and eNOS-dependent manner. This response was blunted by pretreatment with the CYP family 4 inhibitor dibromododecynyl methyl sulfonamide (DDMS) as well as a mechanistically different CYP4 inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (16-HET). Pulmonary arterioles also increased in diameter by 6-12% in the presence of VEGF (10 nM) and this increase was attenuated by DDMS. In contrast to pulmonary arteries, 20-HETE constricted bovine renal arteries and did not increase intracellular calcium in renal artery endothelial cells as observed in bovine pulmonary artery endothelial cells (BPAECs). VEGF evoked increases in [Ca2+]i in BPAECs were blunted by treatment with DDMS. Both VEGF (10 nM) and 20-HETE (1-5µstimulated NO release from cultured bovine PA endothelial cells 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 pulmonary arteries. Given the unique expression of 20-HETE forming CYP4 in PA endothelial cells versus systemic arterial endothelial cells, CYP4 may be an important mediator of endothelial-dependent vasoreactivity in PAs.
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