Figure 4.

Collaterogenesis occurs during the embryonic period. (A) The differentiation of endothelial cells into tip and stalk phenotypes is dependent on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling. (1) Rabep2, whose genetic variations largely determine the differences on collateral extent in murine models, promotes the Rab4 recycling of VEGFR2 to the cell surface, increasing its availability. (2) VEGF binding to VEGFR2 induces endocytosis and signaling which (3) induces delta-like ligand 4 (Dll4). (4) Dll4 activates the transmembrane receptor Notch1, of which the Notch intracellular domain (NICD) is liberated and (5) induces several effects in the adjacent stalk cells, such as cell division. (B) Tip cells are guided by the VEGF gradient and direct the growing sprout while stalk cells follow behind and form the vascular lumen. This process leads to the fusion of two terminal arterioles, forming a new collateral. In the example, a new collateral is forming between terminal branches of the anterior cerebral artery (ACA) to middle cerebral artery (MCA). Rabep2, Rab GTPase-effector binding protein 2; Rab4, Rab GTPase 4.