It is almost intuitive that blood vessels have a central role in biology and medicine. Indeed, even though the concept of blood circulation was not established until a few centuries ago, mankind had known for millennia that blood vessels are indispensable for bringing nourishment to organs and limbs. The converse notion—that growth of blood vessels can promote or facilitate disease—is much more recent. Starting in the mid-nineteenth century, several investigators, including Rudolf Virchow, noted that tumor growth is frequently accompanied by increased vascularity1. Major conceptual advances took place in the 1930s and 1940s, when it was hypothesized that the ability to induce new vessel growth through release of vasoproliferative factors confers a growth advantage on tumor cells2, 3. At about the same time, seminal observations implicating blood-vessel growth in intraocular disorders leading to blindness were made. In 1948, Isaac Michaelson proposed, on the basis of his elegant embryologic and clinicopathological studies, that a diffusible factor (named afterward ‘factor X’) could be responsible not only for the development of the normal retinal vasculature but also for pathological neovascularization in proliferative diabetic retinopathy and other disorders4. Later on, Judah Folkman’s hypothesis that antiangiogenesis could be a strategy to treat cancer and possibly other disorders5 generated a great deal of enthusiasm and gave a major boost to the field. However, harnessing such therapeutic potential first required the isolation, sequencing and cDNA cloning of the mediators of angiogenesis, a major technological challenge in those days.

From neuroendocrinology to angiogenesis and vascular endothelial growth factor I studied Medicine at the University of Catania Medical School, in the homonymous southern Italian city. It was a fortunate circumstance that Umberto Scapagnini had recently joined our medical school as chairman of pharmacology. Attending his lectures planted the seed for my future career. Scapagnini had made important contributions to neuroendocrinology after spending several years at the University of California–San Francisco (UCSF) in the lab of William Ganong, one of the pioneers in this field. While still a medical student, I joined Scapagnini’s group. Wishing to pursue research in the same field, in 1983 I began a postdoctoral fellowship in Richard Weiner’s laboratory in the Reproductive Endocrinology Center at UCSF. While culturing different cell types from bovine pituitary, I stumbled on a population of non–hormone-secreting cells with unusual characteristics6. We identified these cells as follicular cells. The function of follicular cells was poorly understood, but their cytoplasmic projections establish intimate contacts with perivascular spaces, a finding that led some early investigators to suggest that these cells have a role in regulating growth or maintenance of the pituitary vasculature. I was so intrigued by this possibility that I tested follicular cell–conditioned medium on cultured endothelial cells. To my delight, the medium strongly promoted endothelial cell growth7. At that time, basic fibroblast growth factor (bFGF) was thought to be the major endothelial cell mitogen and angiogenic factor in pituitary and other organs. However, in 1986 it became known that bFGF is an intracel-