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
(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,”
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
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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