Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth.
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.
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Xiangjian
X
Zheng
Chong
C
Xu
Annie O
AO
Smith
Amber N
AN
Stratman
Zhiying
Z
Zou
Benjamin
B
Kleaveland
Lijun
L
Yuan
Chuka
C
Didiku
Aslihan
A
Sen
Xi
X
Liu
Nicolas
N
Skuli
Alexander
A
Zaslavsky
Mei
M
Chen
Lan
L
Cheng
George E
GE
Davis
Mark L
ML
Kahn
D000595:Amino Acid Sequence; D000818:Animals; D020785:Central Nervous System Vascular Malformations / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007365:Intercellular Junctions / Q000378:metabolism; D000075927:KRIT1 Protein; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C575920:CCM2L protein, mouse; D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; C480498:osmosensing scaffold for MEKK3 protein, mouse