Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, mechanisms which CLAs poorly understood. Here, we show G12D expression endothelial cells (LECs) during embryonic development impairs formation lymphovenous valves causes enlargement demonstrate primary human LECs induces cell spindling, proliferation, migration. It also increases AKT ERK1/2 phosphorylation decreases genes regulate maturation MEK1/2 inhibition with FDA-approved drug trametinib suppresses -induced morphological changes, Trametinib Cre-mediated a dominant-negative form MEK1 ( Map2k1 K97M ) vessel hyperplasia embryos. Last, conditional knockout wild-type Kras does not affect or function Together, our data indicate KRAS/MAPK signaling must be tightly regulated for proper vessels further support testing inhibitors treating