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From the beginning, arteries and veins are different in the way they branch
into vascular networks, say Dartmouth heart researchers, who have identified a
new defect limited to arterial development.
Michael Simons
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The discovery, reported in the June issue of Developmental Cell, upends
some theories about the origins of blood vessels and could change the nature of
vascular biology research that seeks to harness the mechanisms of blood vessel
growth for treatment.
"This is the first demonstration of a vascular branching defect that is
limited to arteries," says Michael Simons,
professor of medicine and of pharmacology and toxicology at Dartmouth Medical School and chief of
cardiology at Dartmouth-Hitchcock Medical
Center, who led the international team. "It appears that venous and
arterial endothelial cells are fundamentally different from day one. Just
because they are endothelial cells doesn't mean they are the same."
Blood vessel growth, called angiogenesis, is a double-edged sword. It aids
in circulation and wound healing, but also feeds cancer tumors. Most attempts
at therapeutic angiogenesis to stimulate growth of arteries have failed, Simons
notes. One of the reasons may be the tendency to use venous cells to study
potential therapeutic agents. "Our findings indicate that you have to
choose the endothelial cell type to study to fit the question you ask. So, to
think about how to understand the forces of artery formation, we need to study
arterial endothelial cells."
The researchers determined that an intracellular protein synectin is a key
regulator of arterial growth. Using mice and zebra fish, they showed that
disruption of synectin impairs arterial development. Knocking down levels in
zebra fish or eliminating them in mice "resulted in profound reduction in
size and complexity of the arterial network, while remarkably not affecting
venous development," the team reports. The synectin gene is expressed in
every cell type in the body, yet the defect is only arterial.
Homing in on the molecular process, the team found that the synectin
deficient arterial endothelial cells did not make the thin membrane extensions
characteristic of moving cells. Normally, a protein called Rac1 is activated to
initiate the formation of the filaments, called lamellipodia. Synectin
deficient arterial endothelial cells appear to have a defect that prevents the
movement of the activated Rac1 protein to the cell edge to form
lamellipodia.
When arteries are clogged in coronary artery disease, patients form extra
arteries called collaterals to help blood bypass the obstruction. However, some
patients cannot form many collateral arteries, and those patients have more
serious heart disease, Simons explains. Early studies suggest that abnormal
synectin gene expression may explain the absence of extra arteries in some of
the patients.
Coauthors on the study include Thomas W. Chittenden, Anthony A. Lanahan,
Robert T. Palac, Eugene V. Tkachenko, Arye Elfenbein, Arie Horowitz, Mary Jo
Mulligan-Kehoe, Karen L. Moodie, and Zhen W. Zhuang, all from Dartmouth, as
well as researchers from the University of Leuven, Belgium, University of Iowa,
and Eli Lilly and Company.
By HALI WICKNER
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