Notch activation of Ca2+-sensing receptor mediates hypoxia-induced pulmonary hypertension

A recent study from our group demonstrated that the Ca2+-sensing receptor (CaSR) was upregulated and that the extracellular Ca2+-induced increase in the cytosolic Ca2+ concentration [Ca2+](cyt) was enhanced in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic pulmonary arterial hypertension. Here, we examined whether hypoxia-induced activation of Notch signaling leads to the activation and upregulation of CaSR in hypoxia-induced pulmonary hypertension (HPH). The activation of Notch signaling with Jag-1, a Notch ligand, can activate the function and increase the expression of CaSR in acute and chronic hypoxic PASMCs. Downregulation of Notch3 with a siRNA attenuates the extracellular Ca2+-induced increase in [Ca2+](cyt) and the increase in hypoxia-induced PASMC proliferation in acute hypoxic rat PASMCs. Furthermore, we tested the prevention and rescue effects of a gamma-secretase inhibitor (DAPT) in HPH rats. For the Jag-1-treated group, right ventricular systolic pressure (RVSP), right heart hypertrophy (RV/LV+S ratio), and the level of right ventricular myocardial fibrosis were higher than the hypoxia alone group. Meanwhile, DAPT treatment prevented and rescued pulmonary hypertension in HPH rats. The Notch activation of CaSR mediates hypoxia-induced pulmonary hypertension. Understanding the new molecular mechanisms that regulate [Ca2+](cyt) and PASMC proliferation is critical to elucidating the pathogenesis of HPH and the development of novel therapies for pulmonary hypertension.