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 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations.

Methods And Results: 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.

Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations.

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis.

VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). Expression, proteolytic processing, and diffusion range of VEGF proteins need to be tightly regulated, due to their crucial roles in development.