TY - JOUR
T1 - Dynamic Regulation of the Cerebral Cavernous Malformation Pathway Controls Vascular Stability and Growth
AU - Zheng, Xiangjian
AU - Xu, Chong
AU - Smith, Annie O.
AU - Stratman, Amber N.
AU - Zou, Zhiying
AU - Kleaveland, Benjamin
AU - Yuan, Lijun
AU - Didiku, Chuka
AU - Sen, Aslihan
AU - Liu, Xi
AU - Skuli, Nicolas
AU - Zaslavsky, Alexander
AU - Chen, Mei
AU - Cheng, Lan
AU - Davis, George E.
AU - Kahn, Mark L.
N1 - Funding Information:
We thank the members of the Kahn laboratory for their thoughtful comments during the course of this work and Katherine Speichinger and Matthew Davis for their technical assistance. We would also like to thank M. Ginsberg and J.J. Liu for generously providing us with HEG-IC and αIIb-IC beads. These studies were supported by grants from the National Institute of Health (grants R01HL094326 and R01HL102138 to M.L.K., R01HL059373 to G.E.D., and T32HL07971 to X.Z.) and the American Heart Association (grant 11SDG7430025 to X.Z.).
PY - 2012/8/14
Y1 - 2012/8/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865085052&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2012.06.004
DO - 10.1016/j.devcel.2012.06.004
M3 - Article
C2 - 22898778
AN - SCOPUS:84865085052
SN - 1534-5807
VL - 23
SP - 342
EP - 355
JO - Developmental cell
JF - Developmental cell
IS - 2
ER -