The tip cell concept 10 years after: New players tune in for a common theme

The cardiovascular system is the first organ to become functional during vertebrate embryogenesis and is responsible for the distribution of oxygen and nutrients to all cells of the body. The cardiovascular system constitutes a circulatory loop in which blood flows from the heart through arteries into the microvasculature and back through veins to the heart. The vasculature is characterized by the heterogeneity of blood vessels with respect to size, cellular architecture and function, including both larger vessels that are found at defined positions within the body and smaller vessels or vascular beds that are organized in a less stereotyped manner. Recent studies have shed light on how the vascular tree is formed and how the interconnection of all branches is elaborated and maintained. In contrast to many other branched organs such as the lung or the kidney, vessel connection (also called anastomosis) is a key process underlying the formation of vascular networks; each outgrowing angiogenic sprout must anastomose in order to allow blood flow in the newly formed vessel segment. It turns out that during this "sprouting and anastomosis" process, too many vessels are generated, and that blood flow is subsequently optimized through the removal (pruning) of low flow segments. Here, we reflect on the cellular and molecular mechanisms involved in forming the complex architecture of the vasculature through sprouting, anastomosis and pruning, and raise some questions that remain to be addressed in future studies.