Key result
Genetic deletion or pharmacological inhibition of TRPV4 attenuated serotonin-induced pulmonary vasoconstriction and significantly reduced the development of chronic hypoxic pulmonary hypertension in mice.
Why the study?
Does TRPV4 inhibition or genetic deletion reduce serotonin-induced pulmonary vasoconstriction and enhanced vasoreactivity in chronic hypoxic pulmonary hypertension in mice?
Does TRPV4 inhibition or genetic deletion reduce serotonin-induced pulmonary vasoconstriction and enhanced vasoreactivity in chronic hypoxic pulmonary hypertension in mice?
TRPV4 contributes to serotonin-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity seen in chronic hypoxic pulmonary hypertension.
Answers are grounded in this paper and cite their sources.
TRPV4 inhibition may attenuate hypoxic PH in mice; leaves open clinical translation and human trials.
Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4(-/-) mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 μM HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4(-/-) PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca(2+) response was attenuated by HC-067047 in WT PASMCs but not in trpv4(-/-) PASMCs, suggesting TRPV4 is a major Ca(2+) pathway for 5-HT-induced Ca(2+) mobilization. Nifedipine also attenuated 5-HT-induced Ca(2+) response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca(2+) channels in the 5-HT response. Chronic exposure (3-4 wk) of WT mice to 10% O2 caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4(-/-) mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH.
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Xia et al. (2013) studied Chronic hypoxic pulmonary hypertension. TRPV4 genetic deletion (trpv4-/-) or pharmacological inhibition (HC-067047) vs. Wild-type mice or vehicle control was evaluated on Mean pulmonary arterial pressure (PAP) and serotonin-induced pulmonary vasoconstriction (p=<0.05). Genetic deletion or pharmacological inhibition of TRPV4 attenuated serotonin-induced pulmonary vasoconstriction and significantly reduced the development of chronic hypoxic pulmonary hypertension in mice.
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