Abstract 129: Overexpression of P110alpha Induces Vascular Malformation in Mouse Tail, Feet and Ears

Abstract

Phosphoinositide-3 kinases (PI3Ks) are a family of signal transduction enzymes involved in critical cellular functions such as cell growth, proliferation, differentiation, motility and survival. Class IA PI3K is composed of a heterodimer between a P110 catalytic subunit and a p85 regulatory subunit. Upregulation of P110alpha protein significantly propagates second messenger response accelerating Akt signaling. To augment Akt activity in macrophages, we generated mice with conditional myeloid lineage-specific (LysM-Cre) overexpression of P110alpha (M-P110α+). Peritoneal macrophages isolated from these mice expressed an additional band slightly different in size than P110alpha protein and had markedly increased phosphorylation of Akt. These mice also exhibited dramatic changes in blood cells including lower levels of white blood cells, B-cells and an increase in neutrophils; whereas the levels of T-cells and monocytes were not different compared to wild-type mice. Because of the defects of B-cell development, M-P110α+ mice had also splenomegaly with decreased levels of follicles. Unexpectedly, M-P110α+ mice at age of 3-4 weeks spontaneously developed a striking phenotype with massive enlargements of small vessels forming malformations in the extremities including tail, feet and ears. These vascular malformations grew very rapidly, and, at age 5-7 months, M-P110α+ mice developed severe hemorrhages from lesions on the tail and feet. The malformations appeared to be mainly venous by Doppler color ultrasonography, and histologically they represented overgrowth of venous and capillary cells that expressed endothelial markers including CD31/PECAM-1, von Willibrand factor and panendothelial cell antigen, MECA-32. These endothelial cells exhibited high levels of proliferation detected by Ki67 staining. In addition, the malformations were surrounded by high numbers of macrophages. In conclusion, M-P110α+ mice develop spontaneous capillary-venous malformations that represent a novel model of the human PIK3CA-related overgrowth spectrum. This mouse model provides a unique opportunity to develop novel therapeutic strategies to prevent capillary and venous malformations.