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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 normalPKDallele in cystic epithelia and cyst development associated with the unstablePkd2   WS25allele 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 byPkd2gene) expression inPkd2   +/−vessels, roughly half the wild-type level, and an enhanced level of intracranial vascular abnormalities inPkd2 +/−mice when induced to develop hypertension. Consistent with these observations, freshly dissociatedPkd2 +/−vascular smooth muscle cells have significantly altered intracellular Ca2+homeostasis. The resting [Ca2+]iis 17.1% lower inPkd2 +/−compared with wild-type cells (P=0.0003) and the total sarcoplasmic reticulum Ca2+store (emptied by caffeine plus thapsigargin) is decreased (P&lt;0.0001). The store operated Ca2+(SOC) channel activity is also decreased inPkd2 +/−cells (P=0.008). These results indicate that inactivation of just onePkd2allele is sufficient to significantly alter intracellular Ca2+homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca2+store in VSMCs. Based on these findings, and the fact that [Ca2+]isignaling is essential to the regulation of contraction, production and secretion of extracellular matrix, cellular proliferation and apoptosis, we propose that the abnormal intracellular Ca2+regulation associated withPkd2haploinsufficiency is directly related to the vascular phenotype.

Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells