Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein‐kinin system in vascular endothelial cells

Vascular farnesoid X receptor (FXR) ligands have been shown previously to regulate vascular tension. This study investigated whether FXR activation regulates vasoreactivity via the angiotensin II (Ang II) type 2 receptor (AT₂R) and the kallikrein‐kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT₁R), AT₂R, bradykinin type 1/2 receptor (B₁R, B₂R), small heterodimer partner‐1 (SHP‐1) and the endothelial and inducible NO synthases (eNOS/iNOS) were analysed by Western blotting. Real‐time quantitative polymerase chain reaction was performed to analyse expression of eNOS and iNOS mRNA. Kallikrein activity and bradykinin content were assayed using spectrophotometry and a bradykinin assay kit, respectively. Aortic vasoconstriction and vasodilation were also investigated following FXR activation in the presence or absence of AT₂R and B₂R blockade. It was found that the FXR agonists GW4064 and INT‐747, in a dose‐dependent manner, increased the protein abundance of AT₂R, B₂R and SHP‐1 and decreased that of AT₁R. AT₂R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP‐1, B₂R and bradykinin. Moreover, it was found that GW4064 and INT‐747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD123319 and by B₂R blockade with HOE140. The current work suggests that FXR regulates vascular tension by controlling the eNOS‐NO system via activation of a pathway mediated by AT₂R‐B₂R pathway in RAECs.