Angiogenesis before 2000—Cardiovascular system and angiogenesis during the centuries.

Unlike other organs of the human body, the cardiovascular system has attracted human curiosity for its features. Indeed, since ancient times, the beating heart and the red color of blood flowing inside vessels were investigated for anatomical research, but they also inspired metaphorical as well as symbolical interpretations. Thus, for a very long time, the cardiac pump was thought as the seat of passions, leading to the development of the haemocardiocentric theory, especially in Aristotle’s medicine and philosophy. After the long-lasting Galen’s medicine, new anatomical discoveries were made in the Renaissance period, with more correct observations of the cardiovascular system by Leonardo da Vinci and Andreas Vesalius. Descartes’ mechanistic approach confirmed the discovery of blood circulation by William Harvey, whereas histological investigations unrevealed the capillary network. These studies mainly describe blood vessels as static anatomical structures with poor information about their formation and development. At the end of the 18th century, surgeon John Hunter introduced the novel concept of angiogenesis in in vivo experiments, leading to modern embryological research. Thus, the pioneer angiogenesis observations were characterized by the first microscopic evidence of capillary formation and the discovery of the angioblasts by Florence Sabin. A turning point of angiogenesis concept was marked in the 1970s of 20th century with the pivotal works by Judah Folkman and the study of pro- and antiangiogenic factors, which characterized the next two decades of angiogenesis research. New recent models of neovascularization have been proposed, including vasculogenic mimicry and vessel cooption to explain the nonangiogenic tumor growth and the antiangiogenic drug unresponsiveness. Future trends aim to explore the role of the angiogenic process and immunity. © 2026 Elsevier Inc. All rights reserved.