13-P088 Study: The role and regulation of the cytoskeleton during myeloid chemotaxis

Breakdowns of the blood–brain barrier (BBB) are frequently associated with various central nervous system (CNS) diseases. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable microenvironment for the CNS by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-b (TGF-b) signaling, specifically in the cerebral ECs, results in intracranial hemorrhage and BBB breakdown due to defective endothelium–pericyte interaction. The molecular mechanisms underlying the function of Smad4-mediated TGF-b signals in stabilizing the cerebrovascular EC–pericyte interactions had been investigated. Our findings provide a new mechanistic link between TGF-b and Notch signaling pathways in an important physiological system, and have important implications for various CNS diseases related with cerebrovascular dysfunction. The cerebrovascular EC-specific Smad4 knockout mouse could serve as a unique and valuable model for further investigating the potential mechanisms of HHT pathology in brain.