Roles of the Osmo-Mechanosensitive TRPV4 Channel in Chronic Hypoxic Pulmonary Hypertension

摘要

Chronic exposure to hypoxia leads to the development of chronic hypoxic pulmonary hypertension (CHPH). Multiple Ca~(2+) pathways in pulmonary arterial smooth muscle cells (PASMCs) are involved in CHPH development. Previous studies showed that the transient receptor potential (TRP) channels, in particular the TRPC channels, play important roles in CHPH. We recently found that among all vanilloid (TRPV) and melastatin (TRPM) related TRP channels, the osmo-mechanosensitive TRPV4 is the only channel upregulated in pulmonary arteries (PAs) of chronic hypoxic rats. Mechanical stress (imposed by hypotonic solution) activated Ca~(2+) response was potentiated in PASMCs, and myogenic tone was enhanced in pressurized PAs of hypoxic rats. Furthermore, the development of CHPH, right heart hypertrophy and vascular remodelling were significantly delayed and suppressed in hypoxic trpv4~(-/-) mice. These novel findings suggest that TRPV4 is an important signal pathway critical for the development and maintenance of CHPH.