title: Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions.
abstract: Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity, and vascular remodeling, which are associated with alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries (PAs) of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1(-/-) and Trpc6(-/-)) mice compared with wild-type after exposure to 10% O(2) for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1(-/-) and Trpc6(-/-) mice. Small PAs of normoxic wild-type mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1(-/-) PAs, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6(-/-) PAs, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the augmented vasoreactivity was attenuated in Trpc1(-/-) and eliminated in Trpc6(-/-) PAs. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of microvessels were further suppressed in TRPC1-TRPC6 double-knockout mice. Our results, therefore, provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes, and that the presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension in the mouse model.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. jsks@jhmi.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Yang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Fu
authors.forename: Omkar
authors.initials: O
authors.lastname: Paudel
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: James S K
authors.initials: JS
authors.lastname: Sham
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000503:physiopathology*; D050052:TRPC Cation Channels / Q000235:genetics*; D000074287:TRPC6 Cation Channel; D014666:Vasomotor System / Q000503:physiopathology*
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C096351:transient receptor potential cation channel, subfamily C, member 1
keywords: TRPC1 channel; TRPC6 channel; hypertension, pulmonary; hypoxia; vascular smooth muscle