title: Time-dependent phenotypic and contractile changes of pulmonary artery in chronic hypoxia-induced pulmonary hypertension.
abstract: Phenotypic and contractile changes in pulmonary arterial smooth muscle cells (PASMCs) were examined in rats with pulmonary hypertension induced by hypoxia. Exposure to hypoxia induced pulmonary hypertension within 1-4 weeks. Staining with BrdU revealed that proliferative activities of PASMCs peaked at 1 week of hypoxic exposure, and then moderate proliferative activity was maintained for the next 2-4 weeks. The beta-actin/alpha-actin ratio also increased at 1-2 weeks of exposure to hypoxia. Absolute contractility of the pulmonary arterial ring continuously decreased during hypoxia, whereas the basal active tonus of the pulmonary artery increased at 1-3 weeks. Nicardipine, the ETA-receptor antagonis, CI-1034 and the rho-kinase inhibitor Y27632 partially inhibited the elevated active tonus. Endothelin-1 content in the pulmonary hypertensive lung was continuously increased during exposure to hypoxia. In conclusion, the hypoxia-induced proliferative activity of PASMCs comprised a transient phase followed by a sustained phase. The change in PASMCs from a contractile to a synthetic phenotype also correlated with proliferative activity, which subsequently decreased PASMC contractility. The continuous production of endothelin-1 upon hypoxic exposure might contribute to the increased basal tonus of the pulmonary arterial wall, which might subsequently increase pulmonic arterial pressure, resulting in accelerated pulmonary hypertension.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Aoshima
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation; D019332:Endothelin-1 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia; D007150:Immunohistochemistry; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology; D010641:Phenotype; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000199:Actins; D000577:Amides; D019332:Endothelin-1; C419982:PD 180988; D011725:Pyridines; D013843:Thiazines; C108830:Y 27632; D009529:Nicardipine