Title | Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Zheng X, Xu C, Smith AO, Stratman AN, Zou Z, Kleaveland B, Yuan L, Didiku C, Sen A, Liu X, Skuli N, Zaslavsky A, Chen M, Cheng L, Davis GE, Kahn ML |
Journal | Dev Cell |
Volume | 23 |
Issue | 2 |
Pagination | 342-55 |
Date Published | 2012 Aug 14 |
ISSN | 1878-1551 |
Keywords | Amino Acid Sequence, Animals, Central Nervous System Vascular Malformations, Embryo, Mammalian, Gene Expression Regulation, Developmental, Intercellular Junctions, KRIT1 Protein, Mice, Mice, Knockout, Microfilament Proteins, Microtubule-Associated Proteins, Molecular Sequence Data, Neovascularization, Pathologic, Protein Binding, Proto-Oncogene Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction |
Abstract | Cardiovascular 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. |
DOI | 10.1016/j.devcel.2012.06.004 |
Alternate Journal | Dev Cell |
PubMed ID | 22898778 |
Grant List | R01HL102138 / HL / NHLBI NIH HHS / United States R01HL094326 / HL / NHLBI NIH HHS / United States R01HL059373 / HL / NHLBI NIH HHS / United States T32HL07971 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Benjamin Kleaveland, M.D., Ph.D.