Enhanced Ca2+-Sensing Receptor Function in Idiopathic Pulmonary Arterial Hypertension

RATIONALE:A rise in cytosolic Ca concentration ([Ca]cyt) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca]cyt and enhanced Ca influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). OBJECTIVE:We examined whether the extracellular Ca-sensing receptor (CaSR) is involved in the enhanced Ca influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. METHODS AND RESULTS:In normal PASMC superfused with Ca-free solution, addition of 2.2 mmol/L Ca to the perfusate had little effect on [Ca]cyt. In IPAH-PASMC, however, restoration of extracellular Ca induced a significant increase in [Ca]cyt. Extracellular application of spermine also markedly raised [Ca]cyt in IPAH-PASMC but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca-induced [Ca]cyt rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH-PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca-mediated [Ca]cyt increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. CONCLUSIONS:The extracellular Ca-induced increase in [Ca]cyt due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension.