Finding could lead to new approach for treating severe heart disease

December 03, 2000

UCSF researchers report that a new approach for delivering the potent growth factor VEGF into mice with coronary heart disease prompted the growth of blood vessels in damaged heart tissue, without causing side effects, offering hope for a treatment strategy for coronary heart disease that until now has met with setbacks.

The finding is reported in the current issue of Proceedings of the National Academy of Science.

VEGF, or vascular endothelial growth factor, induces the growth of blood vessels throughout the body, and researchers believe that it could be used therapeutically to induce blood vessel growth, or angiogenesis, in heart muscle that has been damaged by lack of oxygen, as occurs in coronary heart disease. Increased blood flow, and thus oxygen, into heart muscle could rejuvenate oxygen-deprived cells.

This kind of treatment for severe coronary heart disease could prove valuable, because while present treatments - angioplasty, a procedure that involves cleaning out clogged arteries, and coronary bypass surgery - are often helpful, renarrowing, or restinosis, of coronary vessels occurs in 30 to 35 percent of cases.

Numerous techniques for introducing VEGF into failing heart muscle in animals and humans have prompted blood vessel formation and improved circulation in damaged tissue. However, each strategy has had short-lasting effects, caused an immunologic reaction, or led to the formation of angiomas, or tumors.

In previous human studies, injection of VEGF protein into ailing heart muscle caused only a fleeting angiogenic response, as a protein's life span is short. Injection of the VEGF gene via a molecule of DNA known as a plasmid, caused the development of angiomas. And insertion of the VEGF gene via a common cold virus known as adenovirus prompted an immunologic reaction in heart muscle cells, leading to inflammation, which in turn causes arrhythmia, or abnormal heart rhythm.

In the UCSF study, researchers used an adeno-associated viral vector to transport a human form of the VEGF gene into the heart muscle of mice. The vector was injected into several sites of damaged heart muscle, as well as into one site of normal, healthy heart muscle. Unlike adenovirus, adeno-associated virus is not known to cause any human disease.

The VEGF gene was expressed in normal and damaged tissues. But VEGF protein, produced by the gene, prompted the growth of new blood vessels only in damaged tissue. Notably, the adeno-associated viral vector did not prompt an inflammatory cell response, or the development of angioma-like structures.

"These results indicate that the adeno-associated viral vector may be an ideal mode for delivering the VEGF gene into the heart muscle," says the lead author of the study, Hua Su, MD, assistant research physician in the UCSF Cardiovascular Research Institute and a member of the UCSF laboratory of senior author Yuet Wai Kan, MD, DSc, Louis K. Diamond Professor of Hematology, UCSF professor of laboratory medicine, and a Howard Hughes Medical Institute Investigator.

"The finding demonstrates that the adeno-associated virus vector can mediate efficient gene transfer and adequate gene expression, and that VEGF gene delivered by this mechanism can induce angiogenesis in damaged heart muscle. Plasmid and adenoviral vectors, by contrast, apparently cause overly high expression of the VEGF gene."

The fact that blood vessel formation did not occur in normal tissue may be explained by emerging evidence that oxygen levels regulate VEGF gene and receptor expression. Recent studies suggest that hypoxic, or low-oxygen level, conditions not only induce the expression of VEGF, but also up-regulate the expression of VEGF receptors, through which VEGF proteins act. If this proves to be the case, the reverse would also be true - the higher levels of oxygen in healthy tissue would induce fewer VEGF receptors, thus diminishing the activity of VEGF proteins and the induction of angiogenesis.

The levels of VEGF gene expression in the UCSF study were adequate to induce angiogenesis, yet mild enough not to cause side effects. However, under actual therapeutic conditions, where the viral vector would be expected to work over the course of many months or years, side effects could arise, says Su.

With this in mind, the researchers plan to investigate in a mouse model whether oxygen levels do regulate the expression of the VEGF gene and receptor. If they do, the researchers will attempt to incorporate a hypoxia-response element, found in VEGF genes, into the adeno-associated viral vector, so that the VEGF gene would express its protein only in the presence of hypoxic cells. Such a regulatory factor could protect against the danger of prolonged and high-level expression of the VEGF gene -the development of angiomas.
-end-
The other co-author of the study is Ronghua Lu, PhD, UCSF visiting assistant researcher in the UCSF Cardiovascular Research Institute and a member of the Kan lab.

The study was funded by the Howard Hughes Medical Institute.

University of California - San Francisco

Related Blood Vessels Articles from Brightsurf:

Biofriendly protocells pump up blood vessels
In a new study published today in Nature Chemistry, Professor Stephen Mann and Dr Mei Li from Bristol's School of Chemistry, together with Associate Professor Jianbo Liu and colleagues at Hunan University and Central South University in China, prepared synthetic protocells coated in red blood cell fragments for use as nitric oxide generating bio-bots within blood vessels.

Specific and rapid expansion of blood vessels
Upon a heart infarct or stroke, rapid restoration of blood flow, and oxygen delivery to the hypo perfused regions is of eminent importance to prevent further damage to heart or brain.

Flexible and biodegradable electronic blood vessels
Researchers in China and Switzerland have developed electronic blood vessels that can be actively tuned to address subtle changes in the body after implantation.

Lumpy proteins stiffen blood vessels of the brain
Deposits of a protein called ''Medin'', which manifest in virtually all older adults, reduce the elasticity of blood vessels during aging and hence may be a risk factor for vascular dementia.

Cancer cells take over blood vessels to spread
In laboratory studies, Johns Hopkins Kimmel Cancer Center and Johns Hopkins University researchers observed a key step in how cancer cells may spread from a primary tumor to a distant site within the body, a process known as metastasis.

Novel function of platelets in tumor blood vessels found
Scientists at Uppsala University have discovered a hitherto unknown function of blood platelets in cancer.

Blood vessels can make you fat, and yet fit
IBS scientists have reported Angiopoietin-2 (Angpt2) as a key driver that inhibits the accumulation of potbellies by enabling the proper transport of fatty acid into general circulation in blood vessels, thus preventing insulin resistance.

Brothers in arms: The brain and its blood vessels
The brain and its surrounding blood vessels exist in a close relationship.

Feeling the pressure: How blood vessels sense their environment
Researchers from the University of Tsukuba discovered that Thbs1 is a key extracellular mediator of mechanotransduction upon mechanical stress.

Human textiles to repair blood vessels
As the leading cause of mortality worldwide, cardiovascular diseases claim over 17 million lives each year, according to World Health Organization estimates.

Read More: Blood Vessels News and Blood Vessels Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.