CDC42 Deletion Elicits Cerebral Vascular Malformations via Increased MEKK3-Dependent KLF4 Expression

Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications, however, the cellular and molecular events governing vascular malformations are not yet fully understood. Objective: Here, we investigated the role of CDC42 during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. Methods and Results: In order to avoid secondary systemic effects often associated with embryonic gene deletion we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCM). At the cellular level, loss of CDC42 function in brain endothelial cells (EC) impairs their sprouting, branching morphogenesis, axial polarity and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where ...