Genome sequencing efforts have identified causative mutations for different types of malformations and opened up possibilities for therapeutic intervention specifically targeting the aberrant signal transduction pathways 2, 3. These diseases commonly arise from abnormalities in the endothelial cells (ECs) of the affected vessel type(s) that lead to structural and functional vascular defects causing deformation, pain, morbidity, and organ dysfunction 1.
Vascular malformations are chronic, often congenital pathologies that can manifest in different types of blood and lymphatic vessels. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. In the postnatal vasculature, PIK3CA H1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Using a mouse model of PIK3CA H1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. Here we show that the somatic PIK3CA H1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Cellular mechanisms underlying LM pathology are poorly understood. Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic).