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 Dr. 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 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, they found, "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 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.
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