Farnesoid X Receptor Activation Modulates Calcium Homeostasis in Rat Aortic Vascular Smooth Muscle Cells

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is expressed in the vasculature; our previous work showed that FXR regulated vascular reactivity through NO mechanism. The underlying mechanism for the regulation of vascular tension by FXR remains unclear. The present work was designed to investigate whether FXR regulates calcium homeostasis in aortic vascular smooth muscle cells (VSMCs). Protein abundances of angiotensin II type 1 and 2 receptors (AT₁R, AT₂R), bradykinin type 1 and 2 receptors (B₁R, B₂R), and the inositol 1,4,5-trisphosphate receptor (IP₃R) were analyzed by western blotting. Kallikrein activity and bradykinin content were assayed by using spectrophotometry and a bradykinin assay kit, respectively. Aortic contraction, intracellular Ca²⁺ concentrations ([Ca²⁺]i), sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) activities, and IP₃-evoked Ca²⁺ release were investigated, following FXR activation in the presence or absence of AT₂R and B₂R blockade. We found that the FXR agonists GW4064 and INT-747 increased the protein abundance of AT₂R and B₂R in rat aortic VSMCs. AT₂R blockade with PD123319 reversed the effects of FXR agonists on kallikrein activity, B₂R, and bradykinin levels. Moreover, we found that GW4064 and INT-747 decreased intracellular [Ca²⁺], increased SERCA activity, downregulated IP₃R₁ expression, and attenuated IP₃-induced Ca²⁺ release. These effects were partially reversed by AT₂R and B₂R blockade with PD123319 and HOE140, respectively. Our data suggest that FXR regulates vascular tension by modulating extracellular Ca²⁺ influx and intracellular Ca²⁺ release from the sarcoplasmic reticulum via activation of an AT₂R-B₂R pathway in rat aortic VSMCs.