UNC scientists uncover crucial mechanism for blood vessel development

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UNC scientists uncover crucial mechanism for blood vessel development

CHAPEL HILL -- New research at the University of North Carolina at Chapel

Hill provides insights into the fundamental mechanisms controlling blood

vessel formation and may have implications for therapies such as

non-surgical restoration of circulation.

The study findings appear in the June 15 issue of the journal Blood.

Blood vessel formation, or angiogenesis, is an integral part of normal organ

development and function. It also contributes to abnormal conditions,

particularly tumor formation and growth.

Angiogenesis begins with the establishment of an intricately branched

rudimentary network called the vascular plexus, which is assembled from

blood vessel precursor cells. This is followed by increased cell division of

specific cells, endothelial cells that make up the lining of blood vessels.

These cells then sprout and migrate away from the parent vessel, and the

sprouts ultimately connect with each other, allowing the vessel network to

expand. This process is called sprouting angiogenesis.

" It is very important to understand the sprouting process, because it occurs

any time there is angiogenesis, whether for helpful reasons, such as wound

healing, or in the context of pathology, such as cancer, " said Dr.

L. Bautch, who is a member of the School of Medicine's Carolina

Cardiovascular Biology Center and a professor of biology at the university.

Angiogenesis is coordinated by the actions of a number of proteins, and one

of the most critical regulators of this process is the protein Vascular

Endothelial Growth Factor-A, or VEGFA, said Bautch. Sprouting angiogenesis

occurs as a result of the interactions of VEGFA with two cell receptor

molecules, VEGFR1 (also called flt-1) and VEGFR2 (also called flk-1), she

added.

While flk-1 is thought to promote endothelial cell division, the exact

functions of flt-1 are poorly understood and have been difficult to uncover

until now, said Bautch.

Research by Bautch's group reveals for the first time that flt-1 positively

controls sprouting by regulating endothelial cell migration.

UNC co-authors postdoctoral researcher ph Kearney and graduate student

Kappas measured the efficiency of vessel formation using mouse

embryonic stem cells genetically engineered to lack the flt-1 gene and then

induced to become endothelial cells.

Mutant and normal embryonic stem cells were additionally engineered to

express the green fluorescent protein. This " marker " allows fluorescence

microscopy to visualize living cells.

The experiment enabled the researchers to analyze the dynamics of vessel

formation in real time by performing time-lapse imaging of live endothelial

cells. Using this method they demonstrated that blood vessels made from

cells lacking the flt gene are defective in sprouting and that these sprouts

migrate less quickly. These findings may have implications for future

therapies.

" For instance, coronary heart disease, which is commonly treated by bypass

surgery, requires reconstruction of blood vessels using veins from other

parts of the body, " said Bautch. " Diabetes is another pathological condition

associated with loss of circulation in the limbs and extremities. "

The goal of angiogenic therapy in these situations is to restore circulation

non-surgically.

" There have been attempts to induce blood vessel formation by manipulating

the VEGF molecular pathway. Most of the time you don't get functional

vessels, but a set of dilated vessels that haven't made the right

connections, " said Bautch.

" We, along with others, are now beginning to unravel the complexity of this

pathway. We think the flt-1 receptor actually regulates the amount of VEGFA

required for proper vessel formation. So having the right amount of VEGF at

the right spot and in the right context is critical, " she added. Department

of biology co-authors, along with Bautch, Kearney and Kappas, were Catharina

Ellerstrom and DiPaola.