A one-in-three batting average is a major league player's dream. It's not so great when referring to the number of patients who must return to the operating room after vascular surgery. Yet one in three patients require multiple operations to eliminate post-operative buildup of scar tissue inside blood vessels.

In fact there's an element of injury in every invasive procedure. In all forms of cardiovascular reconstruction, including angioplasty and bypass grafting, this injury induces wound healing-particularly in smaller blood vessels. Dr. Alexander Clowes, professor of surgery and head of the Division of Vascular Surgery, studies the biology of the vascular response to injury.

"The bottom line is that one-third of these patients are going to get into trouble again," says Clowes. "It's frustrating to all of us doing reconstructions. I'm very interested in making my reconstructions last."

Blood vessel walls consist of layers of smooth muscle cells and elastin. Smooth muscle cells normally contract and relax the wall.

In response to injury, the smooth muscle cells are activated. The rapidly dividing smooth muscle cells migrate through the elastic layers to form a thick layer inside the hollow vessel. The cells and associated matrix reduce or prevent blood flow in a blood vessel, similar to blockages in atherosclerosis-commonly referred to as "hardening of the arteries."

In the 1970s UW researchers led by the late Dr. Russell Ross discovered platelet-derived growth factor (PDGF), a substance which stimulates smooth muscle cells to multiply and migrate through the elastic layers after injury. To examine the relationship between smooth muscle cells and PDGF, Clowes studies arteries treated with bypass grafts or stents. Surgeons implant stents into the narrow parts of arteries to keep them open. After implantation, the stents, resembling woven Chinese fingertraps, are incorporated into the scar tissue. "Our research with stents indicates that we're right on the threshold of some very new therapies that will control the smooth muscle cell response," says Clowes.

Another molecule of interest in Clowes' smooth muscle cell research is the epidermal growth factor receptor (EGFR). EGFR is important in assembling and organizing all of the information coming into the cell. Heparin, a blood-thinning drug taken to increase blood circulation, inhibits smooth muscle cell growth and migration by interfering with EGFR function. Clowes suggests there's a possibility of a new class of drugs that would block the EGF receptors to suppress the thickening/narrowing of the arteries.

"Pharmacology based on our understanding of basic biologic mechanisms is going to be very effective," Clowes says. "One of the interesting things we're finding is that injury reactivates the embryotic program again to rebuild the blood vessel. We want to control this injury response."

In the process of understanding the mechanism and biology of injury, Clowes and his colleagues have developed an antibody that blocks PDGF, thereby preventing the migration and overgrowth of smooth muscle cells in injured blood vessels. This antibody, in the form of an injection, might someday be given to patients undergoing reconstructive surgery.

"The antibody we developed is a mouse antibody, so it would be immunogenic-a foreign protein-to humans," says Clowes. "Using genetic engineering, most of the mouse protein is replaced by human antibody IgG. This humanized antibody effectively blocks the human PDGF receptor but does not elicit an immune response. It is currently being tested in clinical trials."

Pharmacology, not radiation, is going to be very effective in preventing the overgrowth of smooth muscle cells, he explains. Radiation, an alternative therapy, kills or suppresses the growth. The critical weakness of radiation is that it actually induces proliferation of smooth muscle cells, particularly at the boundaries of the zone of radiation.

Most forms of reconstructive vascular surgery date back to World War II or thereafter. "The surgical approach for blood vessel reconstruction will be with us indefinitely," says Clowes. "The focus now is on making it work better."

Clowes received his M.D. cum laude for research in biophysics from Harvard Medical School in 1972. He completed a residency in surgery at University Hospitals of Cleveland, Case Western Reserve University and served as a research fellow in pathology at Harvard Medical School. In 1979 Clowes was a clinical fellow in vascular surgery at the Peter Bent Brigham Hospital in Boston. Clowes joined the UW School of Medicine in 1980 as an assistant professor of surgery. From 1992 to 1993, he was acting chair of the Department of Surgery.