Protein Could Help Rejuvenate Oxygen-Starved Cardiac Tissue, Heal Wounds

The finding, reported in the October 1 issue of Genes & Development, is a notable advance in an effort that has met with setbacks. Researchers have tried to generate the production of healthy blood vessels by inducing over-expression of the growth factor VEGF. But studies in mice have shown that while over-expression of VEGF induces the growth of blood vessels, the capillaries are leaky, the tissues are inflamed and swollen, and the blood vessels have an abnormal “corkscrew-like” shape.

In the current study, researchers genetically engineered mice to overexpress the HIF-1á gene in skin cells. In response, the number of capillaries in the mice’s skin increased by nearly 70 percent. More importantly, the blood vessels did not leak, cause swelling or inflammation.

“The vessels looked like normal capillaries,” says senior author Jeffrey M. Arbeit, MD, UCSF associate professor of surgery, and a member of the UCSF Comprehensive Cancer Center. “This finding, together with the fact that the vessels didn't leak, is extremely exciting.” The increase in healthy blood vessels was evident in the mice’s significantly pinker ears, paws and tails.

Notably, in the current study the overexpression of the HIF-1á gene caused a 13-fold increase in the expression of the VEGF gene. The fact that HIF-1á had an effect on VEGF expression is not surprising in itself, as HIF-1á is a sub unit of the HIF-1 transcription factor, which regulates the expression of numerous genes, including VEGF. However, the finding does prompt the question of why the blood vessels were robust, given that previous studies involving elevated expression of VEFG led to the development of weak, leaky vessels.

“We know that VEGF plays a crucial role in blood vessel growth. We need to determine how overexpression of HIF-1á harnesses VEGF in a way that could be beneficial therapeutically,” says lead author David Elson, BA, UCSF staff research associate in the Arbeit lab.

The potential clinical implications of the finding are significant. The HIF-1á gene is already being explored as a stimulant to promote blood vessel growth in oxygen-deprived, or ischemic, tissue such as that associated with diabetic peripheral vascular disease, which can cause chronic leg ulcers that often precipitate amputation. It is being investigated as therapy to increase blood flow into cardiac tissue deprived of oxygen due to clogged arteries, and as therapy to treat recalcitrant wounds resulting from lack of blood flow to the legs caused by atherosclerosis alone or in association with diabetes. It could also be used to promote the grafting of artificial skin into tissues of the body, either in burn or diabetic patients. Once a graft had fused with the skin, the gene could be “turned off.”

On the flip side, HIF-1á could prove a potent target for cancer therapy. Malignant tumors must recruit blood vessels to fuel their growth. Scientists have known that HIF-1á is over-expressed by malignant tumors, and NIH investigators currently are exploring its potential as a therapeutic target. However, the gene’s specific role in cancer development has not been known. The discovery that overexpression of the gene generates the growth of robust blood vessels will assist ongoing therapeutic studies.

There are various possible explanations for why the new blood vessels in the UCSF study were robust despite the elevated expression of VEFG, says Elson. In the current study, over-expression of HIF-1á caused the induction of the naturally occurring VEGF gene. In previous studies, scientists engineered the expression of various splici