Cerebral cavernous malformations (CCMs) are common, familial vascular malformations that cause strokes and seizures in midlife. Due to their location in the brain CCMs are virtually untreatable, making the development of novel therapies a priority. Positional cloning studies have identified mutations in three novel proteins, CCM1, CCM2 and CCM3, which interact biochemically but have no defined function. Convergent studies in zebrafish have shown that mutations in a novel cell surface receptor Heart of Glass (Heg), zCCM1, or zCCM2 give rise to a dilated heart during embryonic development. These studies identify a novel signaling pathway that regulates cardiovascular development and causes human vascular disease, but how this pathway functions is unknown. To begin to investigate this question, we have generated Heg-deficient and CCM2-deficient mice. We find that CCM2-/- and Heg-/-;CCM2 animals exhibit vascular defects and die prior to E10.5, while Heg-/- animals exhibit cardiac and vascular defects later in gestation and after birth. CCM2 knockdown blocks endothelial cord formation ex vivo and endothelial adherens junctions are abnormally shortened in the dilated chambers of fish lacking Heg or CCM2. We hypothesize that Heg receptors signal via CCM proteins in endothelial cells to regulate cardiovascular development and homeostasis by controlling cell-cell association. This proposal will test this hypothesis by addressing the following questions: i. What are the early developmental defects in CCM2-/- and Heg-/-;CCM2 mouse embryos? ii. What is the role of Heg-CCM signaling in endothelial, smooth muscle and cardiac muscle cells during cardiovascular development? iii. Do Heg receptors associate with CCM proteins at endothelial cell-cell junctions to regulate the formation and function of lumenized vascular structures? iv. Does CCM pathogenesis reflect an ongoing requirement for Heg-CCM signaling in the mature vasculature or are CCMs late manifestations of subtle developmental defects? The answers to these questions will provide new insight into vascular development and take the first steps toward the creation of new therapies for a human vascular disease.

Public Health Relevance

This proposal will investigate a novel signaling pathway that regulates vascular and heart development in vertebrates and is also the basis of a common human vascular disease known as cerebral cavernous malformation. Understanding how this pathway functions in the developing embryo, in adult mice and in endothelial cells are the major goals of this project. Our studies will provide the knowledge necessary to better understand cardiovascular development and develop new treatments for a cardiovascular disease that affects tens of thousands of Americans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094326-05
Application #
8402622
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2009-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$371,102
Indirect Cost
$135,482
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zheng, Xiangjian; Riant, Florence; Bergametti, Fran├žoise et al. (2014) Cerebral cavernous malformations arise independent of the heart of glass receptor. Stroke 45:1505-9
Zheng, Xiangjian; Xu, Chong; Di Lorenzo, Annarita et al. (2010) CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations. J Clin Invest 120:2795-804
Kleaveland, Benjamin; Zheng, Xiangjian; Liu, Jian J et al. (2009) Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat Med 15:169-76