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

doi:10.1016/j.devcel.2012.06.004

Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth

Dev Cell. 2012 Aug 14;23(2):342-55. doi: 10.1016/j.devcel.2012.06.004.

Authors

Xiangjian Zheng¹, 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

Affiliation

¹ Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Central Nervous System Vascular Malformations / embryology
Central Nervous System Vascular Malformations / genetics
Central Nervous System Vascular Malformations / metabolism*
Embryo, Mammalian / blood supply
Embryo, Mammalian / metabolism
Gene Expression Regulation, Developmental
Intercellular Junctions / metabolism
KRIT1 Protein
Mice
Mice, Knockout
Microfilament Proteins / chemistry
Microfilament Proteins / deficiency
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Microtubule-Associated Proteins / chemistry
Microtubule-Associated Proteins / deficiency
Microtubule-Associated Proteins / metabolism*
Molecular Sequence Data
Neovascularization, Pathologic*
Protein Binding
Proto-Oncogene Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction

Substances

CCM2L protein, mouse
KRIT1 Protein
Krit1 protein, mouse
Microfilament Proteins
Microtubule-Associated Proteins
Proto-Oncogene Proteins
osmosensing scaffold for MEKK3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding