Nitric-oxide-mediated zinc release contributes to hypoxic regulation of pulmonary vascular tone.
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 microm/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.
Bernal
Paula J
PJ
Center for Biological Imaging, Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Leelavanichkul
Karanee
K
Bauer
Eileen
E
Cao
Rong
R
Wilson
Annette
A
Wasserloos
Karla J
KJ
Watkins
Simon C
SC
Pitt
Bruce R
BR
St Croix
Claudette M
CM
D000818:Animals; D001011:Aorta / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008668:Metallothionein / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009569:Nitric Oxide / Q000502:physiology*; D015538:Nitrosation; D009928:Organ Specificity; D010100:Oxygen / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D015032:Zinc / Q000502:physiology*
D002614:Chelating Agents; D005029:Ethylenediamines; D009569:Nitric Oxide; D008668:Metallothionein; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D010100:Oxygen