Shear stress and pathophysiological PI3K involvement in vascular malformations

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain -of -function (GOF) mutations in the gene encoding the catalytic alpha subunit of PI3K alpha ( PIK3CA ). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA -related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA - related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA 's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA 's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast -flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.