title: The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression.
abstract: The cerebral cavernous malformation (CCM) pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations, but its molecular effectors are not well defined. Here we show that loss of CCM signaling in endocardial cells results in mid-gestation heart failure associated with premature degradation of cardiac jelly. CCM deficiency dramatically alters endocardial and endothelial gene expression, including increased expression of the Klf2 and Klf4 transcription factors and the Adamts4 and Adamts5 proteases that degrade cardiac jelly. These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells. MEKK3 is both necessary and sufficient for expression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. These findings reveal a molecular mechanism by which CCM signaling controls endothelial gene expression during cardiovascular development that may also underlie CCM formation.
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Zinan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Rawnsley
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Goddard
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Xing-Jun
authors.initials: XJ
authors.lastname: Cao
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Jakus
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.affiliation: Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Whitehead
authors.affiliation: Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
authors.forename: Dean
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Genetics, Pediatric, and Medicine (Cardiology) and Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; Lab of Cardiovascular Signaling, Centenary Institute, Sydney NSW 2050, Australia. Electronic address: x.zheng@centenary.org.au.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address: markkahn@mail.med.upenn.edu.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004699:Endocardium / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse