Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 110, Issue 2, Pages 182-190Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.09059FP
Keywords
pulmonary artery; hypoxia; contraction; endothelin-1; proliferation
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Funding
- Program for the Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN)
- Japanese Ministry of Education, Culture, Sports, Science, and Technology
- Grants-in-Aid for Scientific Research [21380178] Funding Source: KAKEN
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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 I 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 I - 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 I - 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.
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