Vessel quality, not quantity, vital

March 1, 2006

The emphasis on blood vessel quantity over quality might explain why efforts to grow new vessels in patients with ischemic complications by simply supplying cells with VEGF have fared poorly.

London - To heal wounds, blood vessel quality may be more important than blood vessel quantity, according to research by Holger Gerhardt, Ph.D., head of the vascular biology laboratory at Cancer Research UK in London.

In mouse models of oxygen-induced retinopathy, Dr. Gerhardt and Andrea Lundkvist, a post-doctoral colleague, have shown that blood vessel regeneration involves vascular endothelial growth factor A (VEGFA). More significantly, VEGFA is secreted by neighboring cells and forms a gradient that guides the proper patterning of growing blood vessels.

"The last decades in angiogenesis research have largely dealt with blood vessel quantity and identification of many factors that either promote or inhibit formation of new blood vessels," Dr. Gerhardt tells Dermatology Times. "But few people have been looking carefully at quality."

"If you inject VEGF into the eye so that you simply increase its levels," Dr. Gerhardt explains, "you lose directionality of the response. You can get massive vasodilation and proliferation but no directional vessel growth."

Angiogenesis is a normal biochemical process that is especially active during early development and wound healing. But studies have shown that disease or inflammatory processes interfere with normal healing. Through manipulating the process, Dr. Gerhardt hopes to enhance the body's own healing ability to treat diseases in which normal angiogenesis has gone awry.

VEGF is an important biochemical in blood vessel growth. It is produced by nervous system cells, such as astrocytes, and its levels are controlled by oxygen. But exactly how VEGF regulates growth had been largely unexplored.

As a new vessel grows, it is perfused by blood and the surrounding tissue is oxygenated. This reduces levels of VEGFA where new vessels have been established. High levels of VEGFA persist ahead of the vessel, creating a VEGFA gradient. The leading endothelial cells, known as tip cells, grow in the direction of the gradient.

Dr. Gerhardt's research also suggests that VEGFA directs the trailing endothelial cells, or stalk cells, but in a different manner - it stimulates them to divide. Consequently, the shape of the gradient balances the tip-cell and stalk-cell response, and thereby defines the direction and diameter of the newly formed sprout.

Recently scientists at the University of California, Los Angeles, led by Luisa Iruela-Arispe, published a study in the Journal of Cell Biology (May 2005 23;169(4):681-691) suggesting that proteases cleave VEGF, which disrupts gradient formation.

Work by Dr. Gerhardt confirms this finding. In mouse retinas, localized ischemia triggers protease activity. This appears to disperse the growth factor and disrupt the gradient. Preliminary data suggest that inhibiting protease activity restores guided neovascularization. Research to confirm these findings is ongoing.

In the future, compounds designed to block the relevant proteases might treat various diseases and also aid therapies in which angiogenesis is involved.

Diabetics, for example, are at high risk of retinopathy. After a phase of ischemia, new blood vessels grow in an attempt to replace lost or leaky vessels in the retina. Often, however, newly formed vessels fail to reestablish a functional network and can grow in the wrong places such as the vitreous of the eye. This can cause bleeding, fibrosis and retinal detachment.

Paradoxically, improving the quality of blood vessels that feed tumors may also be beneficial, says Dr. Gerhardt. High-quality vessels may provide a better conduit to deliver drugs directly into tumors.