The development of chronic hypoxia (CH)-induced pulmonary hypertension is associated with increased pulmonary arterial smooth muscle cell (PASMC) Ca²⁺ influx through acid sensing ion channel 1 (ASIC1) and activation of the Ca²⁺/calcineurin-dependent transcription factor, nuclear factor of activated T-cells isoform c3 (NFATc3). Whether Ca²⁺-influx through ASIC1 contributes to NFATc3 activation in the pulmonary vasculature is unknown. Furthermore, both ASIC1 and calcineurin have been shown to interact with the scaffolding protein, protein interacting with C kinase 1 (PICK1). In the present study, we tested the hypothesis that ASIC1 contributes to NFATc3 nuclear translocation in PASMC in a PICK1-dependent manner. Using both ASIC1 knockout (ASIC1^-/-) mice and pharmacological inhibition of ASIC1, we demonstrate ASIC1 contributes to CH (1 wk @ 380 mmHg) and endothelin-1 (ET-1; 10^-7 M) induced Ca²⁺ responses and NFATc3 nuclear import in PASMC. The interaction between ASIC1/PICK1/calcineurin was shown using Duolink in situ proximity ligation assay. Inhibition of PICK1, using FSC231, abolished ET-1- and ionomycin-induced NFATc3 nuclear import, but did not alter ET-1-mediated Ca²⁺ responses suggesting that PICK1 acts downstream of Ca²⁺ influx. The key findings of the present work are that 1) Ca²⁺ influx through ASIC1 mediates CH- and ET-1-induced NFATc3 nuclear import and 2) the scaffolding protein, PICK1, is necessary for NFATc3 nuclear import. Together these data provide an essential link between CH-induced ASIC1-mediated Ca²⁺ influx and activation of the NFATc3 transcription factor. Identification of this ASIC1/PICK1/NFATc3 signaling complex increases our understanding of the mechanisms contributing to the vascular remodeling and increased vascular contractility associated with CH-induced pulmonary hypertension.