The main findings of this study are as follows: (1) CPA-induced depletion of ER Ca2+ induces an endothelium-dependent dilation that requires activation of SOCE; (2) this vasorelaxation upon CPA-induced depletion of ER Ca2+ mainly relies on EDH; (3) both NKA and NCX are involved in the vasorelaxation through the CPA/SOCE/EDH mechanism; and (4) the CPA/SOCE/EDH-mediated vasorelaxation is defective in colitis. Here, TAC1 is linked to colitis.