201. Dynamic Regulation of the Cerebral Cavernous Malformation Pathway Controls Vascular Stability and Growth
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Mei Chen, Amber N. Stratman, Aslihan Sen, Alexander Zaslavsky, George E. Davis, Chong Xu, Mark L. Kahn, Benjamin Kleaveland, Chuka Didiku, Zhiying Zou, Lan Cheng, Lijun Yuan, Nicolas Skuli, Annie O. Smith, Xiangjian Zheng, and Xi Liu
- Subjects
medicine.medical_treatment ,Molecular Sequence Data ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Vasculogenesis ,Proto-Oncogene Proteins ,medicine ,Animals ,Amino Acid Sequence ,KRIT1 Protein ,Molecular Biology ,Central Nervous System Vascular Malformations ,Mice, Knockout ,Neovascularization, Pathologic ,Sequence Homology, Amino Acid ,Growth factor ,Microfilament Proteins ,Gene Expression Regulation, Developmental ,Cell Biology ,Embryo, Mammalian ,Cell biology ,Endothelial stem cell ,Vascular endothelial growth factor B ,Vascular endothelial growth factor A ,Intercellular Junctions ,Vascular endothelial growth factor C ,Signal transduction ,Wound healing ,Microtubule-Associated Proteins ,Sequence Alignment ,Protein Binding ,Signal Transduction ,Developmental Biology - Abstract
SummaryCardiovascular growth must balance stabilizing signals required to maintain endothelial connections and network integrity with destabilizing signals that enable individual endothelial cells to migrate and proliferate. The cerebral cavernous malformation (CCM) signaling pathway utilizes the adaptor protein CCM2 to strengthen endothelial cell junctions and stabilize vessels. Here we identify a CCM2 paralog, CCM2L, that is expressed selectively in endothelial cells during periods of active cardiovascular growth. CCM2L competitively blocks CCM2-mediated stabilizing signals biochemically, in cultured endothelial cells, and in developing mice. Loss of CCM2L reduces endocardial growth factor expression and impairs tumor growth and wound healing. Our studies identify CCM2L as a molecular mechanism by which endothelial cells coordinately regulate vessel stability and growth during cardiovascular development, as well as postnatal vessel growth.
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