Upregulated Calcium Sensing Receptor Mediates Pulmonary Venous Remodeling in Pulmonary Hypertension

Abstract

Aim: The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH).

Methods: PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced Ca²⁺ influx and proliferation in PVSMCs and whether CaSR mediates PVR.

Results: PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular Ca²⁺ restoration induced a huge increase in [Ca²⁺]_i in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [Ca²⁺]_i and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular Ca²⁺-induced [Ca²⁺]_i increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [Ca²⁺]_i in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia.

Conclusions: Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular Ca²⁺ signaling is an important pathogenic mechanism underlying the development of PVR in PH.

Keywords: calcium sensing receptor; pulmonary hypertension; pulmonary veins; pulmonary venous remodeling; pulmonary venous smooth muscle cells.