Cerebral cavernous malformations (CCMs) are common, familial vascular malformations that arise due to mutations in three genes, KRIT1, CCM2 and PDCD10. Adaptor proteins encoded by the CCM genes bind each other and the cell surface receptor, Heart of Glass (HEG). Genetic studies in mice have revealed that HEG-CCM signaling is required in endothelial cells for early vascular development, while dilated hearts in deficient fish have also suggested that CCM signaling guides heart development and growth. How CCM signaling alters endothelial cell function in the setting of cardiovascular development and CCM disease remains unclear. We have used a new Nfatc1Cre allele to delete CCM signaling exclusively in the endocardium of the heart, thereby bypassing the requirement for this pathway in early vessel growth. We find that endocardial loss of CCM signaling results in heart failure associated with loss of cardiac jelly and over-expression of the ADAMTS5 protease and the KLF2 transcription factor. Reduced expression of either gene rescues the heart defects in ccm-deficient fish, demonstrating causal, functional roles for these new downstream CCM signaling effectors. The present proposal will define this new pathway downstream of CCM signaling by (i) testing CCM regulation of cardiac and vascular matrix, (ii) defining the role of CCM regulation of KLF2 in cardiac development and vascular disease models, and (iii) testing the hypothesis that CCM signaling affects matrix and KLF2 and ADAMTS5 gene expression through regulation of MEKK3 activity and MAPK signaling. These studies are expected to yield new insight into how the endocardium regulates cardiac development, and how CCM signaling affects endothelial cell function in the context of cardiovascular development and vascular disease.

Public Health Relevance

This proposal investigates a newly discovered role for the Cerebral Cavernous Malformation pathway in heart development. This pathway is known to cause human vascular malformations, but the mechanism by which it does so is not understood. Our studies reveal a new role for the pathway in the developing heart, and new molecular information regarding how the pathway works in endothelial cells. These findings are therefore relevant to both cardiac development and the pathogenesis of vascular malformations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094326-07
Application #
8963474
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2009-01-01
Project End
2018-10-31
Budget Start
2015-11-01
Budget End
2016-10-31
Support Year
7
Fiscal Year
2016
Total Cost
$360,000
Indirect Cost
$135,000
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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