July 12, 2004

New Research Suggests Previously Unrecognized Mechanism by Which Blood Vessels Are Patterned
Using an Animal Model, Penn Researchers Identify Receptor in Endothelial Cells
That Is Crucial for Cardiovascular Development

(Philadelphia, PA) – Congenital heart disease (CHD) is a leading cause of mortality in children worldwide. According to the American Heart Association, Congenital cardiovascular defects are present in about one percent of live births and are the most common malformations in newborns. Researchers from the University of Pennsylvania School of Medicine have recently identified new signaling pathways that may lead to a better understanding of how this deadly disease forms. Jonathan Epstein, MD, Associate Professor of Medicine and the study’s lead investigator, identified a receptor in endothelial cells (the cells that line blood vessels) that when interrupted in mice, results in CHD and defects in the growth and arrangement of blood vessels (patterning). “With the identification of this receptor, we hope to one day develop molecular medicines that will essentially steer developing blood vessels away from where they shouldn’t go,” said Epstein.

This finding – published in the July 2004 issue of Developmental Cell – may lay the groundwork for discovering ways to diagnose and prevent CHD. In an accompanying article in Developmental Cell, Epstein and collaborators at the National Institutes of Health demonstrated the pathways that they have discovered are functional in diverse organisms, including fish. In the larger picture, the researchers suggest this work may be crucial in determining why blood vessels migrate to certain destinations in the body.

The researchers engineered mice with an inactivated endothelial receptor, called PlexinD1. These mice had structural cardiovascular defects involving the outflow vessels of the heart, which resembled a common form of CHD in children and caused perinatal deaths of PlexinD1 deficient mice.

The type of CHD caused by inactivation of PlexinD1 in mice has previously been attributed to abnormalities of neural crest cells, which are important in setting up the correct arrangement of tissue in a developing embryo. “With this research, we have been able to show that this form of CHD can be caused by defects within the cells that line blood vessels. This research could lead to new ways to modify the growth of blood vessels because this receptor seems to tell blood vessels in which direction they should grow,” says Epstein. With this finding, researchers hope to one day be able to manipulate where blood vessels go, which may lead to the development of therapies for any disease in which the presence of blood vessels is unwanted, including diabetic retinopathy and many types of tumors.

Other Penn researchers contributing to this study are Aaron D. Gitler and Min-Min Lu. This study was funded by grants from the National Institutes of Health and the American Heart Association.

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PENN Medicine is a $2.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report), a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home health care and hospice.

This release is available online at http://www.uphs.upenn.edu/news/News_Releases/july04/PlexinReceptor.htm