![]() ![]() ![]() Rapamycin and its analogues (sirolimus, everolimus) that target the PI3K downstream effector mTOR can stop the progression of vascular malformations in mice and human, and improve the patients’ quality of life 3, 5, 15, 16, 17, 18, 19. Identification of PIK3CA mutations as drivers of vascular malformations has opened up a possibility for the therapeutic use of PI3K inhibitors in these diseases. Conversely, conditional expression of the PIK3CA-activating mutation in endothelial cells led to vascular overgrowth and malformations in mice 4, 5, 15, 16. ![]() Genetic loss-of-function studies in mice demonstrated an important role of p110α in the development of both blood and lymphatic vessels 12, 13, 14. Of the four p110 isoforms, the ubiquitously expressed p110α has emerged as the key downstream effector of growth factor receptor signaling in most cell types and in particular in the endothelium. The PI3K lipid kinases control a variety of cellular functions and developmental and homeostatic processes in response to extracellular signals by regulating the plasma membrane phorphatidylinositol (3,4,5)-triphosphate (PIP 3) levels 11. Both types of mutations result in basal activation of the PI3K pathway by enhancing dynamic events in the natural activation of p110α that lead to increased lipid binding 10. The most common VM/LM mutations affecting the helical domain (E542K, E545K) or the kinase domain (H1047R, H1047L) of p110α are identical to those previously found in cancer and other genetic syndromes characterized by tissue overgrowth 9. Somatic activating mutations in the PIK3CA gene, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were identified as causative of ~20% of venous malformations (VM) 4, 5, 6, and the majority of lymphatic malformations (LM) 7, 8. 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). ![]()
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