Background: The extracellular Calcium Sensing Receptor (CaSR) is expressed in the vasculature where its roles are still poorly understood. In this study, we investigate the physiopathological roles of the CaSR in the vasculature in a mouse model of vascular smooth muscle cell (VSMC) specific targeted CaSR deletion (SM22α-Cre x LoxP-CaSR) by performing in vitro, ex vivo and in vivo studies. Results: Wild type (WT) and knock-out (KO) mice were identical in size, lifespan, and reproductive capability. In vitro: In the presence of calcifying concentrations of inorganic phosphate (Pi; 3 mM) and Ca2+ (1.8 mM), cultured VSMC from KO mouse aortae showed a significant increase in calcification compared to WT control (24.60±2.84 vs. 0.99±0.90, arbitrary units, p<0.001, N=6-8, Alizarin Red densitometry), while the allosteric CaSR agonist R-568 reduced Pi/Ca2+-dependent calcification in WT, but not KO VSMC. Ex vivo: Wire myography on aortic rings of WT and KO mice demonstrated that aortae from KO mice had significantly narrower luminal diameters compared to those from WT control (950.2±25.6 vs. 1024.7±36.0 µm, p<0.01, N=5-8). Contractile force of KO aortae in response to KCl and phenylephrine (PE) was significantly impaired compared to that of WT control (3.57±0.79 vs. 5.76±1.36 mN p<0.01, N=5-8, 3 µM PE). In vivo: Blood pressure of 3-6 month old KO mice was significantly reduced compared to WT (106±6 vs. 134±7 mm Hg diastolic, p<0.01 and 157±4 vs. 180±5 mm Hg systolic, p<0.05; N=10-11, tail-cuff). Cardiac MRI performed under anaesthesia showed significant heart remodelling of 14 month old KO mice compared to WT control in the form of increased left ventricular ejection fractions (74.3±1.9 vs. 59.0±2.5 %, p<0.01, N=3) and reduced diastolic and end-systolic volumes. Accordingly, heart wet-weight of 18 month old, but not 3 month old, KO mice was higher than that of age-matched WT control, suggesting that the observed heart remodelling progresses with age. (All data mean±SEM, two-tail t-test) Conclusions: Under pathological conditions of elevated Ca2+ and Pi concentrations, loss of CaSR increased in vitro VSMC calcification while CaSR activation with a calcimimetic reduced VSMC calcification. The reduction in contractile force in aortae from KO is consistent with the observed decrease in blood pressure compared to WT control. The reduction of aortic luminal diameter and heart remodelling indicate a compensatory response to the hypotensive phenotype. Together, these data suggest that the vascular CaSR plays an important role in physiology, by influencing blood pressure regulation, and in pathology, by preventing vascular calcification.