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Upregulation of TRPV4 channels in pulmonary arteries (PAs) contribute to chronic hypoxia induced myogenic tone and pulmonary hypertension
Author(s) -
Yang XiaoRu,
Hughes Jennifer M.,
Cao YuanNing,
Flavahan Nicholas A.,
Liedtke Wolfgang,
Sham James S.K.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1213.5
Subject(s) - mechanosensitive channels , pulmonary hypertension , hypoxia (environmental) , trpv4 , downregulation and upregulation , right ventricular hypertrophy , medicine , endocrinology , ruthenium red , chemistry , hypoxic pulmonary vasoconstriction , lung , cardiology , transient receptor potential channel , receptor , ion channel , biochemistry , organic chemistry , oxygen , gene , calcium
Acute reduction in alveolar O 2 causes increase in pulmonary arterial pressure (Ppa) and prolonged hypoxia leads to vascular remodeling and pulmonary hypertension. The initial increase in Ppa may act as a stimulus for the development of pulmonary hypertension, possibly involving mechanosensitive cation channels. We have previously shown that the mechanosensitive TRPV4 channels are highly expressed in rat pulmonary arterial smooth muscle cells (PASMCs). Here we found that the TRPV4 agonist 4α‐PDD and hypotonicity induced significant increase in [Ca 2+ ]i in PASMCs. These responses were inhibited by TRPV4 specific siRNA and the TRPV blocker ruthenium red. Real‐time RT‐PCR and western blot showed that TRPV4 expression was upregulated in PAs. Moreover, 4α‐PDD and hypotonicity induced Ca 2+ responses were enhanced in PASMCs of rats after 4 weeks exposure to 10% O 2 . Significant myogenic tone, sensitive to ruthenium red, was also observed in pressurized pulmonary microvessels (100–200 ID, ≥35 mmHg) of chronic hypoxic but not normoxic rats. In extension of these results, the increase in Ppa (indexed by RVSP) and right heart hypertrophy were significantly attenuated in trpv4 ‐/‐ mice exposed to 1, 2, and 4 weeks of hypoxia. These results suggest the novel concept that TRPV4 channels are upregulated in PASMCs during chronic hypoxia and play significant roles in the development of myogenic tone and pulmonary hypertension.