people who have insufficient arterial growth"—people with coronary disease or peripheral vascular disease with occlusions in their major arteries. "So instead of doing bypass surgery, instead of doing angioplasty, maybe we can induce growth of the arteries."

While researchers from the cardiovascular section are looking for ways to stimulate angiogenesis, others want to learn how to inhibit the process. "If you inhibit the blood supply to the tumor, the hope is the tumor will die," Simons continues. "If you're going to inhibit the active blood supply in an in- flamed joint, then inflammation will go away and you will not have an inflamed joint with a destructive disease. The same applies in certain eye diseases as well—for example in macular degeneration, where you have excessive vascularity of the retina. It becomes permeable to all sorts of proteins and you have damage to the eye."

Helisch and Simons aren't shy about disagreeing with one another in public. But all the group's scientific disagreements are in the same vein—cheerfully competitive and friendly.

The process of angiogenesis begins when endothelial cells lining the inside of blood vessels are alerted that damaged or diseased tissue is in need of new blood vessels. The tissue releases angiogenic growth factors—VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), and others—that activate endothelial cells in nearby blood vessels. Those cells begin dividing, migrating through tiny openings in the blood vessel wall to adjacent tissue, then forming new blood vessels.

Scientists know that there are at least 20 angiogenic growth factors, about 30 natural angiogenesis inhibitors in the body, and more than 300 other angiogenesis inhibitors. There are many pieces to this puzzle. Once researchers have figured out what triggers and regulates angiogenesis, they can develop therapies to control it. Just last year, the Food and Drug Administration approved an angiogenesis inhibitor, bevacizumab (Avastin), for colorectal cancer, and it is

Top, from the left: Mike Simons, Mary Jo Mulligan-Kehoe, and Jannine Walsh. Above Right: Armin Helisch, left, and Nicholas Shworak. Above Left: Lab conversation over lunch.

expected to approve more angiogenesis- inhibiting cancer drugs in the near future. In 1997, the FDA approved the first angiogenesisstimulating drug, becaplermin (Regranex) to treat diabetic foot ulcers. A few other angiogenesis-related therapies were approved in the late 1990s. But scientists have a long way to go before angiogenic therapies are commonplace.

Dartmouth's Angiogenesis Research Center includes basic scientists who are investigating cellular signaling mechanisms and other molecular processes; scientists who do preclinical research; clinicians who develop and test imaging technologies; and clinicians who conduct clinical trials.

"One of the real strengths of the entire group is that we all have different strengths and very different focuses," says Shworak, who works on molecules called heparan sulfate proteoglycans, which control cell signaling in angiogenesis; there are some 30 to 40 stimulators or inhibitors of angiogenesis that seem to be working through these molecules. He also helped to clone syndecan-4, a molecule that Simons's lab works on now. Syndecan is derived from the Greek work syndein, which means to bind. "We counterbalance each other's weaknesses," Shworak adds, "and we

work a lot together on different projects. It makes for a much stronger approach because we can really be multidimensional in our analysis."

Research in angiogenesis or collateral arteries really goes back," says Armin Helisch. "The first evidence actually goes back to the 17th century," when an English physician, Dr. Richard Lower, first described preexisting anastomosis, or the existence of connections, among the arteries in the human heart.

The term "angiogenesis" was coined in 1787 by an English surgeon, Dr. John Hunter, to describe new blood vessels growing in reindeer antlers. In 1935, a Boston pathologist described angiogenesis in the placentas of pregnant monkeys. In 1971, the New England Journal of Medicine published a theory by a Harvard surgeon, Dr. Judah Folkman, that angiogenesis enabled tumors to grow. And in 1975, Folkman and a colleague discovered the first angiogenesis inhibitor. In the 1980s, Folkman's lab identified a substance that stimulated capillary growth as well as a substance that inhibited it.

"Judah Folkman was like the founding father [of angiogenesis] in some ways," says Simons. "But he concentrated on anti-angiogenesis for cancer." Research into the cardiovascular implications of angiogenesis started in the 1990s; Simons was then, and remains still, at the forefront of the field.

Simons has assembled a good team of people who are willing collaborators. "There are no proverbial walls between the labs," says cardiology researcher Arie Horowitz, D.Sc., whose lab focuses on intracellular signaling in endothelial cells. In particular, he studies the role of the PDZ protein synectin, the role of synectin-binding factors in regulating cell migration and endocytosis, and directional cues in endothelial cell migration. "There is a lot of collaboration and mutual help."

Researchers share reagents and other chemicals and often ask each other for advice on lab techniques. The lab