title: Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2.
abstract: Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca²⁺ concentration ([Ca²⁺]cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCC) is an important pathway for the regulation of [Ca²⁺]cyt. The potential role for L- and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K⁺- and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K⁺- and U-46619-induced Ca²⁺ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K⁺- and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltage-dependent L-type α1C-subunit (Cav1.2) and T-type α1H-subunit (Cav3.2) upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2.
authors.affiliation: Department of Medicine, Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Zimnicka
authors.forename: Guillaume
authors.initials: G
authors.lastname: Voiriot
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Ayon
authors.forename: Moumita S R
authors.initials: MS
authors.lastname: Choudhury
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ko
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000096:biosynthesis*; D020747:Calcium Channels, T-Type / Q000096:biosynthesis*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011188:Potassium / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C514350:CACNA1C protein, mouse; C504883:Cacna1h protein, mouse; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D014662:Vasoconstrictor Agents; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011188:Potassium; D002118:Calcium
keywords: calcium channel voltage-dependent L-type α1C-subunit; calcium channel voltage-dependent T-type α1H-subunit; hypoxia; mouse; pulmonary artery; voltage-dependent calcium ion channel