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(Circulation Research. 2008;102:1575.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Nitric Oxide–Mediated Zinc Release Contributes to Hypoxic Regulation of Pulmonary Vascular Tone

Paula J. Bernal, Karanee Leelavanichkul, Eileen Bauer, Rong Cao, Annette Wilson, Karla J. Wasserloos, Simon C. Watkins, Bruce R. Pitt, Claudette M. St. Croix

From the Center for Biological Imaging, Department of Cell Biology and Physiology (P.J.B., S.C.W., C.M.S.C.), and Department of Environmental and Occupational Health (K.L., E.B., R.C., A.W., K.J.W., B.R.P., C.M.S.C.), University of Pittsburgh, Pa.

Correspondence to Claudette M. St. Croix, PhD, Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, BRIDG, 100 Technology Dr, Pittsburgh, PA 15219. E-mail cls13{at}pitt.edu

The metal binding protein metallothionein (MT) is a target for nitric oxide (NO), causing release of bound zinc that affects myogenic reflex in systemic resistance vessels. Here, we investigate a role for NO-induced zinc release in pulmonary vasoregulation. We show that acute hypoxia causes reversible constriction of intraacinar arteries (<50 µm/L) in isolated perfused mouse lung (IPL). We further demonstrate that isolated pulmonary (but not aortic) endothelial cells constrict in hypoxia. Hypoxia also causes NO-dependent increases in labile zinc in mouse lung endothelial cells and endothelium of IPL. The latter observation is dependent on MT because it is not apparent in IPL of MT^–/– mice. Data from NO-sensitive fluorescence resonance energy transfer–based reporters support hypoxia-induced NO production in pulmonary endothelium. Furthermore, hypoxic constriction is blunted in IPL of MT^–/– mice and in wild-type mice, or rats, treated with the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), suggesting a role for chelatable zinc in modulating HPV. Finally, the NO donor DETAnonoate causes further vasoconstriction in hypoxic IPL in which NO vasodilatory pathways are inhibited. Collectively, these data suggest that zinc thiolate signaling is a component of the effects of acute hypoxia-mediated NO biosynthesis and that this pathway may contribute to constriction in the pulmonary vasculature.

Key Words: hypoxic pulmonary vasoconstriction • metallothionein • fluorescence microscopy • endothelial cells

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Nitric Oxide–Mediated Zinc Release: A New (Modulatory) Pathway in Hypoxic Pulmonary Vasoconstriction

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