Embryological cellular origins and hypoxia-mediated mechanisms inPIK3CA-Driven refractory vascular malformations

Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos.

In this study, we investigated the pathogenesis of these malformations by expressing Pik3ca^H1047Rin the CPM. Mice expressing Pik3ca^H1047Rin the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3ca^H1047RupregulatesVegf-aexpression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.