Autosomal-dominant polycystic kidney disease is a multiorgan disease and its vascular manifestations are common and life-threatening. Despite this, little is known about their pathogenesis. Somatic mutations to the normal PKD allele in cystic epithelia and cyst development associated with the unstable Pkd2^WS25 allele suggest a two-hit model of cystogenesis. However, it is unclear if this model can account for the cardiovascular pathology or if haploinsufficiency alone is disease-associated. In the present study, we found a decreased polycystin-2 (PC2, protein encoded by Pkd2 gene) expression in Pkd2^+/− vessels, roughly half the wild-type level, and an enhanced level of intracranial vascular abnormalities in Pkd2   ^+/− mice when induced to develop hypertension. Consistent with these observations, freshly dissociated Pkd2   ^+/− vascular smooth muscle cells have significantly altered intracellular Ca ²⁺ homeostasis. The resting [Ca ²⁺ ] _i is 17.1% lower in Pkd2   ^+/− compared with wild-type cells ( P =0.0003) and the total sarcoplasmic reticulum Ca ²⁺ store (emptied by caffeine plus thapsigargin) is decreased ( P <0.0001). The store operated Ca ²⁺ (SOC) channel activity is also decreased in Pkd2   ^+/− cells ( P =0.008). These results indicate that inactivation of just one Pkd2 allele is sufficient to significantly alter intracellular Ca ²⁺ homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca ²⁺ store in VSMCs. Based on these findings, and the fact that [Ca ²⁺ ] _i signaling is essential to the regulation of contraction, production and secretion of extracellular matrix, cellular proliferation and apoptosis, we propose that the abnormal intracellular Ca ²⁺ regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype.