The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3...

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Genetics

Background:

• The cerebral cavernous malformation (CCM) pathway is crucial for normal cardiovascular development and preventing vascular malformations.
• The precise molecular effectors of the CCM pathway in endothelial cells remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which CCM signaling regulates endothelial gene expression during cardiovascular development.
• To identify the molecular players involved in CCM pathway-mediated control of cardiac development and malformation.

Main Methods:

• Investigated the consequences of CCM signaling loss in endocardial cells of developing embryos.
• Analyzed gene expression changes, focusing on transcription factors and proteases involved in cardiac jelly degradation.
• Assessed the role of MEKK3 kinase activity in regulating CCM-dependent gene expression and cardiac development.

Main Results:

• Loss of CCM signaling in endocardial cells leads to mid-gestation heart failure and premature cardiac jelly degradation.
• CCM deficiency alters endothelial gene expression, upregulating Klf2, Klf4, Adamts4, and Adamts5.
• Increased MEKK3 activity, which binds CCM2, drives these gene expression changes and is necessary and sufficient for their occurrence.
• Partial loss of MEKK3 function rescues cardiac defects in CCM-deficient embryos.

Conclusions:

• CCM signaling controls endothelial gene expression via MEKK3 activity during cardiovascular development.
• This pathway's disruption provides a molecular mechanism for cardiac jelly degradation and may underlie cerebral cavernous malformation pathogenesis.