Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a multi-functional non-selective channel expressed in pulmonary vasculatures. TRPV4 contributes to serotonin- (5-HT-) induced pulmonary vasoconstriction and is responsible in part for the enhanced 5-HT response in pulmonary arteries (PAs) of chronic hypoxia mice. Epoxyeicosatrienoic acid (EET) is an endogenous agonist of TRPV4 and is known to regulate vasoreactivity. The levels of EETs, the expression of cytochrome P450 (CYP) epoxygenase for EET production, and epoxide hydrolase for EET degradation are altered by chronic hypoxia. Here, we examined the role of EET-dependent TRPV4 activation in the 5-HT-mediated PA contraction. In PAs of normoxic mice, inhibition of TRPV4 with a specific inhibitor HC-067047 caused a decrease in the sensitivity of 5-HT-induced PA contraction without affecting the maximal contractile response. Application of the cytochrome P450 epoxygenase inhibitor MS-PPOH had no effect on the vasoreactivity to 5-HT. In contrast, inhibition of CYP epoxygenase or TRPV4 both attenuated the 5-HT-elicited maximal contraction to a comparable level in PAs of chronic hypoxic mice. Moreover, the inhibitory effect of MS-PPOH on the 5-HT-induced contraction was obliterated in PAs of chronic hypoxic trpv4−/− mice. These results suggest that TRPV4 contributes to the enhanced 5-HT-induced vasoconstriction in chronic hypoxic PAs, in part via the CYP-EET-TRPV4 pathway. Our results further support the notion that manipulation of TRPV4 function may offer a novel therapeutic strategy for the treatment of hypoxia-related pulmonary hypertension.
Highlights
Chronic hypoxic pulmonary hypertension (CHPH), which belongs to the Group 3 in the pulmonary hypertension classification [1], can be instigated by sustained exposure to hypoxia
These results demonstrate that in normoxia, Cytochrome P450 (CYP) expoxygenasedependent Epoxyeicosatrienoic acid (EET) are not involved in 5-HT-induced pulmonary arteries (PAs) contraction, while Transient receptor potential vanilloid 4 (TRPV4) exhibits modest effect on 5-HTgenerated PA constriction
The major findings are as following: (1) in normoxia, inhibition of TRPV4 with a specific inhibitor HC-067047 caused a decrease in the sensitivity of 5-HT-induced PA contraction, as consistent with previous reports [24], while CYP epoxygenase inhibitor MS-PPOH did not affect vasoreactivity to 5-HT; (2) in chronic hypoxia, blockage of CYP epoxygenase or TRPV4 both attenuated 5-HT-elicited PA contraction to a similar level
Summary
Chronic hypoxic pulmonary hypertension (CHPH), which belongs to the Group 3 in the pulmonary hypertension classification [1], can be instigated by sustained exposure to hypoxia. Increasing evidence indicates that nonselective cation channels affect intrinsic changes in ionic balance and Ca2+ homeostasis in the pulmonary arterial smooth muscle cells and play pivotal roles in acute [2, 3] and prolonged hypoxic responses [4,5,6,7]. TRPV4, serving as an osmo-mechanosensitive channel, is widely expressed and functioning in both systemic and pulmonary vasculatures [9] and is gated by numerous stimuli including moderate heat, shear stress, osmotic, chemical stimuli, and the endogenous agonist, epoxyeicosatrienoic acids (EETs) [8, 10,11,12,13,14,15,16,17,18]. Several mechanisms have been proposed: (1) activation of calcium-activated K+ channels by the diffusion of endothelial-derived EETs to vascular smooth muscle [14]; (2) endothelial TRPV4 activation opens endothelial small and intermediate conductance Ca2+-activated K+ channels, resulting in direct coupling of the endothelium and smooth muscle or the accumulation of K+ in the extracellular space to hyperpolarize the smooth muscle [20]; and (3) TRPV4 coupled with ryanodine receptors and BKCa channels to elicit
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