title: Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction.
abstract: Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40-/-). In vivo, hypoxemia was more severe in Cx40-/- mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40-/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner.
authors.affiliation: The Keenan Research Centre at Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Hannah T
authors.initials: HT
authors.lastname: Nickles
authors.forename: Hannes
authors.initials: H
authors.lastname: Ranke
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Tabeling
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa-Sicard
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
authors.forename: Hee-Sup
authors.initials: HS
authors.lastname: Shin
authors.forename: Songwei
authors.initials: S
authors.lastname: Wu
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Cor
authors.initials: C
authors.lastname: de Wit
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Hermann
authors.initials: H
authors.lastname: Kuppe
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D014661:Vasoconstriction; D000097003:Gap Junction alpha-5 Protein
chemical_list: D015220:Calcium Channels; D017630:Connexins; D054510:Phospholipases A2, Cytosolic; D000097003:Gap Junction alpha-5 Protein