Important roles of the Ca2+ -sensing receptor in vascular health and disease

Ca2+ -sensing receptor (CaSR), a member of G protein-coupled receptor family, is widely expressed in the vascular system, including perivascular neurons, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). When stimulated, CaSR can further increase the cytosolic Ca2+ concentration ([Ca2+](cyt)) in two ways: intracellular Ca2+ release from endo/sarcoplasmic reticulum (ER/SR) and extracellular Ca2+ entry through Ca2+-permeable cation channels. In endothelium, increased Ca2+ subsequently activate nitric oxide synthase (NOS) and intermediate conductance Ca2+ activated K+ channels (IKCa), resulting in vasodilation through NOS-mediated NO release or membrane hyperpolarization. In VSMCs, CaSR-induced intracellular Ca2+ increase causes blood vessel constriction. CaSR activation predominantly induces vasorelaxation of whole vascular tissues through VECs-dependent mechanisms; however, CaSR-induced Ca2+ signaling in VSMCs may play a braking role in CaSR-mediated vasorelaxation. Emerging evidence reveals the importance of CaSR in the regulation of vascular tone and blood pressure. Here, we summarized recent advances in CaSR-mediated vascular reaction and the underlying mechanisms in different species, including humans. In addition, several studies have demonstrated that CaSR dysfunction may be associated with some fatal vascular diseases, such as pulmonary arterial hypertension, primary hypertension, diabetes, acute myocardial infarction and vascular calcification. With the advance of studies on CaSR in vascular health and disease, it is expected positive modulators or negative modulators of CaSR used for the treatment of specific diseases may be promising therapeutic options for the prevention and/or treatment of vascular diseases.