Mekk3 is essential for early embryonic cardiovascular development

The early development of blood vessels consists of two phases, vasculogenes is and angiogenesis, which involve distinct and also overlapping molecular regulators, but the intracellular signal transduction pathways involved in these processes have not been well defined(1-4). We disrupted Map3k3 (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11 family(5,6 ). in mice, Map3k3(-/-) embryos died at approximately embryonic day (E) 11, displaying disruption of blood vessel development and the structural integ rity of the yolk sac. Angiogenesis was blocked at approximately E9.5 in mut ant embryos. Map3k3 disruption did not alter the expression of the genes en coding Vegf-1, angiopoietin or their receptors. The development of embryoni c, but not maternal, blood vessels in the placentas of Map3k3(-/-) embryos was impaired, revealing an intrinsic defect in Map3k3(-/-) endothelial cell s. Moreover, Mekk3 activated myocyte-specific enhancer factor 2C (Mef2c), a transcription factor crucial for early embryonic cardiovascular developmen t through the p38 mitogen-activated protein kinase (Mapk) cascade. We concl ude that Mekk3 is necessary for blood vessel development and may be a possi ble target for drugs that control angiogenesis.