UF Study Reveals Flood Of Proteins Promotes Scarring In Vein Grafts

May 12, 2004

GAINESVILLE, Fla. — Surgeons at the University of Florida and the Malcom Randall Veterans Affairs Medical Center are a step closer to understanding what promotes scarring in vein grafts designed to reroute blood through the legs after key arteries become blocked.

The problem has stymied doctors for years. Circulatory troubles that stem from obstructed arteries in the legs are a substantial cause of pain, disability and limb loss in patients with diabetes and other conditions, accounting for more than 130,000 operations in the United States each year.

Like coronary bypass grafts designed to restore blood flow to the heart after arteries become clogged with fatty plaque, vein grafts in the legs improve the passage of oxygen-rich blood through the lower extremities. But 20 percent of these patients suffer a perplexing complication: Scar tissue frequently forms in the new grafted vessels within months of the operation, eventually occluding them. Within five years, 60 percent of patients have this problem.

Now UF researchers, who studied a rabbit model, report in this month’s Journal of Vascular Surgery that they have hit on a possible reason. An army of proteins that descends to help aid graft healing sometimes proves overzealous – triggering an invasion of white blood cells that cause excessive scarring. Veins in the legs, where blood flows at lower pressure, appear more susceptible to this damage than arteries that move blood under much higher pressures near the heart.

“When bypass scarring occurs, the patient can develop gangrene, and further bypass in these patients is risky,” said Dr. Scott A. Berceli, an assistant professor of vascular surgery at UF’s College of Medicine and the VA Medical Center. “Native blockages develop over decades, but vein bypasses have a more accelerated process of blockage. What our laboratory is focusing on is understanding what are the basic chemical mediators or chemical pathways through which the scarring process occurs, with an aim within several years time of developing drugs and other therapies that can inhibit the scarring process.”

Berceli’s collaborators included UF surgeon Dr. C. Keith Ozaki, and Gregory S. Schultz, who directs UF’s multidisciplinary Institute for Wound Research. The study was funded in part by the National Institutes of Health, the William J. von Liebig Foundation, the Whitaker Foundation, the Howard Hughes Foundation and the Association for Academic Surgery.

The proteins that appear to control the scarring process are called matrix metalloproteinases. Using a rabbit model, researchers examined the relationship between the biomechanical forces associated with blood flow rate and the cellular adaptations that occur in the lining of vein grafts after surgery to a carotid artery, the main artery in the neck that supplies blood to the brain. They discovered that under low-flow conditions, the veins were more prone to scarring. The change was related to an increase in matrix metalloproteinase-2. The presence of a related protein, matrix metalloproteinase-9, also was noted in both low-flow and high-flow conditions, but these changes were not associated with significant increases in protein concentration.

Eventually scientists hope to devise treatments that would enable them to administer corrective genes or medications to switch off the cascade of proteins and white blood cells that go beyond healing to cause scarring in low-flow conditions.

It will take more research before the findings are confirmed in people and before such therapies could be tested in them, Berceli said.

“Vein bypass graft stenosis has been the limiting factor for the success of bypass surgery for decades, and a similar process causes failure of stents,” said Dr. Robert W. Thompson, a professor of surgery and cell biology and physiology at the Washington University in St. Louis School of Medicine. “Dr. Berceli’s work sheds new light on how vein grafts develop scar tissue and narrow and that certain matrix metalloproteinases may be especially important in this. Because drug approaches to inhibit metalloproteinases are available, it seems quite feasible to consider testing these ideas in the near future. Most importantly, this new study helps to explain the mechanisms linking low blood flow in a bypass graft with scarring and begins to dissect out the molecules involved.”