Evolution of angiogenesis.

Endothelial cells, which are the main agents of the angiogenic process in vertebrates, are lacking in the vessels of invertebrates. These are limited by the basement membranes of epithelial or myoepithelial cells. This fact leads to the questions of how vessels grow in invertebrates and how vertebrate angiogenesis evolved. We herein review the knowledge available about vascular growth in invertebrates. The cases described include the ascidian Botryllus, the annelid Hirudo and the squid Idiosepius. All these processes of vascular growth in invertebrates show substantial differences with the vertebrate angiogenesis, although the signalling system mediated by VEGF and its receptor VEGFR seems to be involved in all cases. However, VEGF signalling is used by many processes of cell directional migration, and it cannot be considered as a hallmark of angiogenesis. We also describe the close similarity between the molecular control of the endothelial angiogenesis and the branching morphogenesis of the tracheal system of insects. In both cases, the process is regulated by hypoxia and activates a leading tip cell which inhibits responsiveness of the adjacent cells through a Delta/Notch signalling pathway. We suggest that endothelial angiogenesis in vertebrates arose through cooption of this hypoxia-sensing mechanism by replacing the FGF/FGFR axis of insects by a VEGF/VEGFR-mediated system, and adding a second layer of control of the endothelial state (quiescent or activated) mediated by angiopoietins and Tie receptors. This evolutionarily new control mechanism of endothelial angiogenesis establishes an endothelial/perivascular cell crosstalking which does not exist in invertebrates.