Up‐regulation of TRPV4 Channels in Pulmonary Arteries of Chronic Hypoxic Pulmonary Hypertensive Rats.

TRPM (melastatin‐like) and TRPV (vanilloid‐related) channels belong to the superfamily of TRP channels, which are non‐selectively cation channels with diverse physiological functions. We recently demonstrated the coexistence of multiple TRPM and TRPV subtypes in rat pulmonary arteries (PAs) with TRPM8 and TRPV4 being the most abundant functional TRPM and TRPV channels, respectively. Here we sought to determine the effects of chronic hypoxia on the expression and activity of TRPM and TRPV channels in de‐endothelialized PAs of rats. Real‐time RT‐PCR showed that the expression of TRPV4 mRNA was significantly upregulated, whereas TRPM3, TRPM8, TRPV1 and TRPV2 mRNA were downregulated in PAs of rats exposed to 10% O 2 for 3–4 weeks. Western blot analysis verified that the expression of TRPV4 protein was increased, and TRPM8 protein was reduced in hypoxic PAs. The TRPV4 agonist 4α‐phorbol 12,13‐didecanoate (4α‐PDD) caused significant increase in cation entry measured by Mn 2+ quenching of fura‐2 and by Ca 2+ transients in PASMCs of chronic hypoxic rats. Moreover, hypotonicity induced mechanical stretch, a known stimulus for TRPV4 channels, activated significantly larger Ca 2+ response in chronic hypoxic PASMCs. Our results hence show that chronic hypoxia caused significant alterations in the expression of TRPM and TRPV channels, and the upregulation of TRPV4 may contribute to hypoxic pulmonary hypertension.