(Hypertension. 2001;37:322.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Reduced Hypoxic Pulmonary Vascular Remodeling by Nitric Oxide From the Endothelium
From the First Department of Internal Medicine (M.O., S.K., T.Y., Y.O., Y.R., N.I., K.-I.H., M.Y.) and the First Department of Pathology (Y.H., H.I.), Kobe University School of Medicine, Kobe, Japan.
Correspondence to Seinosuke Kawashima, The First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp
We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca2+-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 µm) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.
Key Words: nitric oxide • nitric oxide synthase • hypoxia • hypertension, experimental • remodeling
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