Dynamic Regulation of the Cerebral Cavernous Malformation Pathway Controls Vascular Stability and Growth

Xiangjian Zheng, Chong Xu, Annie O. Smith, Amber N. Stratman, Zhiying Zou, Benjamin Kleaveland, Lijun Yuan, Chuka Didiku, Aslihan Sen, Xi Liu, Nicolas Skuli, Alexander Zaslavsky, Mei Chen, Lan Cheng, George E. Davis, Mark L. Kahn

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish
Pages (from-to)342-355
Number of pages14
JournalDevelopmental cell
Volume23
Issue number2
DOIs
StatePublished - Aug 14 2012

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