Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells

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 þ/� vessels, roughly half the wild-type level, and an enhanced level of intracranial vascular abnormalities in Pkd2 þ/� mice when induced to develop hypertension. Consistent with these observations, freshly dissociated Pkd2 þ/� vascular smooth muscle cells have significantly altered intracellular Ca 2þ homeostasis. The resting [Ca 2þ ]i is 17.1% lower in Pkd2 þ/� compared with wild-type cells (P ¼ 0.0003) and the total sarcoplasmic reticulum Ca 2þ store (emptied by caffeine plus thapsigargin) is decreased (P < 0.0001). The store operated Ca 2þ (SOC) channel activity is also decreased in Pkd2 þ/� cells (P ¼ 0.008). These results indicate that inactivation of just one Pkd2 allele is sufficient to significantly alter intracellular Ca 2þ homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca 2þ store in VSMCs. Based on these findings, and the fact that [Ca 2þ ]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 2þ regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype.