Polycystin 1 is required for the structural integrity of blood vessels

Autosomal dominant polycystic kidney disease (ADPKD), often caused by mutat ions in the PKD1 gene, is associated with life-threatening vascular abnorma lities that are commonly attributed to the frequent occurrence of hypertens ion. A previously reported targeted mutation of the mouse homologue of PKD1 was not associated with vascular fragility, leading to the suggestion that the vascular lesion may be of a secondary nature. Here we demonstrate a pr imary role of PKD1 mutations in vascular fragility. Mouse embryos homozygou s for the mutant allele (Pkd1(L)) exhibit s.c. edema, vascular leaks, and r upture of blood vessels, culminating in embryonic lethality at embryonic da y 15.5. Kidney and pancreatic ductal cysts are present. The Pkd1-encoded pr otein, mouse polycystin 1, was detected in normal endothelium and the surro unding vascular smooth muscle cells. These data reveal a requisite role for polycystin 1 in maintaining the structural integrity of the vasculature as well as epithelium and suggest that the nature of the PKD1 mutation contri butes to the phenotypic variance in ADPKD.