Scientists find protein can protect new blood vessels from leaking ---promising complement togrowth stimulant VEGF

December 20, 1999

A protein recently found to increase blood vessel growth now appears to protect vessels from leaking as well, a potential boon to treatments for chronic inflammatory diseases and for new therapies that grow healthy blood vessels in damaged hearts and limbs.

The protein, known as angiopoietin-1, or Ang1, can restore leaky vessels to normal, block the effects of substances that make vessels leaky, and complement the action of another natural blood vessel growth stimulant known as VEGF, researchers at UC San Francisco and Regeneron Pharmaceuticals, Inc. report in the December 24 issue of Science. (VEGF stands for vascular endothelial growth factor, the focus of current clinical trials to increase blood vessel growth in limbs and hearts with inadequate blood supplies.)

The new findings, based on studies of blood vessels in the skin of mice, "raise the possibility that a combination of VEGF and Ang1 could have additive effects in promoting angiogenesis (the growth of new blood vessels) plus the added beneficial effect of forming non-leaky vessels," the authors state in the Science paper. Some patients experience tissue swelling due to blood vessel leakage after VEGF treatment, the scientists note.

The concern is not about vessels leaking blood, but rather plasma, the part of blood that lacks red blood cells. Plasma leakage can occur in inflammation as mild as a reaction to a mosquito bite or as severe as chronic arthritis and asthma. Treatments for plasma leakage are few and side effects of treatments are many, the scientists point out.

In terms of the potential for Ang1 in angiogenesis therapy, "the combination of the two growth factors seems to work better than either one alone," explains Gavin Thurston, PhD, assistant adjunct professor of anatomy at UCSF and lead author of the Science paper. "Some patients treated with VEGF experience tissue swelling due to plasma leakage, and this condition can lead to a cascade of other problems. Our study shows that Ang1 can likely prevent this leakage."

VEGF and Ang1 are the only natural growth-inducing proteins shown to act specifically on the cells that line blood vessels - endothelial cells. VEGF was identified more than ten years ago; Ang1, just three years ago.

Thurston and senior author, Donald M. McDonald, MD, PhD, and UCSF professor of anatomy, performed the experiments that led to the new finding with George Yancopoulos, MD, PhD, and other scientists of Regeneron Pharmaceuticals, Inc., a Tarrytown, NY-based biotechnology company where Ang1 was discovered.

The new studies reported in the paper examined the effects of Ang1 and VEGF, separately and together, on the performance of blood vessels in the skin of mice. The mice were genetically modified to overproduce the growth-inducing proteins in the skin, where the effects on blood vessel leakage could be observed.

The studies confirmed that each protein boosts blood vessel growth. However, while VEGF alone led to new vessels that were leaky, Ang1 alone had no such effect, and more strikingly, prevented the leakage effect of VEGF as well as other substances that normally make vessels leak.

Together, the two proteins seem to offer the best of both worlds, the scientists concluded. VEGF spurs new, small vessels to grow, and Ang1 helps the vessels mature. As an added bonus, Ang1 appears to neutralize VEGF's leakage-inducing effect.

Blood vessel leakiness is a common and potentially serious problem in clinical medicine. "It is found in eye diseases that can lead to blindness, as well as in asthma, chronic bronchitis, arthritis and other chronic inflammatory conditions," said McDonald whose UCSF laboratory carried out many of the study's experiments.

"Many substances have been identified that can cause vessel leakage and subsequent swelling, but only a few things do the opposite. And those drugs that do counter swelling, such as glucocortico steroids, often have serious side effects. Ang1 is a natural growth factor in the body, and it now seems like a strong candidate to counter swelling without harmful side effects."

While the new finding holds strong promise for therapeutic benefits, the authors stress the need to determine whether Ang1 can exert its anti-leakage effect in disease conditions.

"We are working to deliver Ang1 to leaky vessels in otherwise normal mice," Thurston says. By extending the research in this way, the scientists hope to move Ang1 closer to use as a therapeutic agent for leaky blood vessels, as well as to learn more about how it exerts its effects on endothelial cells.

Co-authors on the Science paper and research collaborators with Thurston, McDonald and Yancopoulos include Chitra Suri, PhD, a scientist, and Joyce McClain, research associate, both at Regeneron Pharmaceuticals; Kelly Smith, research associate in anatomy and the Cardiovascular Research Institute at UCSF; and Thomas Sato, PhD, at the University of Texas, Southwestern Medical Center in Dallas.

In addition to his professorship at UCSF, McDonald is an investigator in the UCSF Cardiovascular Research Institute. Yancopoulos is senior vice president, research, and chief scientific officer at Regeneron.

The research was funded in part by the National Heart, Lung and Blood Institute of the National Institutes of Health.

University of California - San Francisco

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