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Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels that contribute to cellular excitability. We previously reported that ASIC1 in pulmonary artery smooth muscle cells (PASMC) contribute to pulmonary vasoreactivity and vascular remodeling during the development of chronic hypoxia (CH)-induced pulmonary hypertension. However, the roles of ASIC2 and ASIC3 in regulation of pulmonary vasoreactivity and the development of CH-induced pulmonary hypertension are unknown. We tested the hypothesis that ASIC2 and ASIC3 contribute to increased pulmonary vasoreactivity and development of CH-induced pulmonary hypertension using ASIC2- and ASIC3-knockout ( −/− ) mice. In contrast to this hypothesis, we found that ASIC2 −/−  mice exhibit enhanced CH-induced pulmonary hypertension compared with WT and ASIC3 −/−  mice. This response was not associated with a change in ventilatory sensitivity or systemic cardiovascular function but was instead associated with direct changes in pulmonary vascular reactivity and pulmonary arterial morphology in ASIC2 −/−  mice. This increase in reactivity correlated with enhanced pulmonary arterial basal tone, elevated basal PASMC [Ca 2+ ] and store-operated calcium entry (SOCE) in PASMC from ASIC2 −/−  mice. This increase in PASMC [Ca 2+ ] and vasoreactivity was dependent on ASIC1-mediated Ca 2+  influx but was not contingent upon an increase in ASIC1 mRNA or protein expression in PASMC from ASIC2 −/−  mice. Together, the results from this study demonstrate an important role for ASIC2 to regulate pulmonary vascular reactivity and for ASIC2 to modulate the development of CH-induced pulmonary hypertension. These data further suggest that loss of ASIC2 enhances the contribution of ASIC1 to overall pulmonary vascular reactivity.    NEW &amp; NOTEWORTHY This study demonstrates that loss of ASIC2 leads to increased baseline pulmonary vascular resistance, enhanced responses to a variety of vasoconstrictor stimuli, and greater development of hypoxic pulmonary hypertension. Furthermore, these results suggest that loss of ASIC2 enhances the contribution of ASIC1 to pulmonary vascular reactivity.

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension