MicroRNAs Control Vascular Endothelial Growth Factor Signaling

Angiogenesis is a very tightly controlled process, in which endothelial cells need to migrate and proliferate toward ischemic tissue. A long-known factor that provides a gradient for endothelial cells to migrate toward is vascular endothelial growth factor (VEGF).1 Carefully titrated levels of VEGF are crucial for blood vessel development, because even the heterozygous deletion of VEGF is lethal in mice.2 In the past decades, it has become clear that VEGF signaling is very complex, with different VEGF isoforms and VEGF receptors that tightly control endothelial cell behavior. Interestingly, although VEGF receptor 2 (kinase insert domain receptor [KDR]) is one of the main proangiogenic VEGF receptors,3 binding of VEGF to VEGF receptor 1 (fms-related tyrosine kinase 1 [FLT1]) does not result in proangiogenic signaling, which raised the concept that FLT1 acts as a trap or decoy for VEGF. Thus, FLT1 can negatively regulate VEGF signaling, and this is of crucial importance, for instance, to keep the cornea avascular,4 but also aids in controlling the fine balance between proangiogenic and antiangiogenic factors. To make matters more complex, FLT1 mRNA is alternatively spliced, giving rise to a membrane-bound FLT1 and secreted soluble FLT1,5 but they both function as VEGF traps, preventing VEGF from activating KDR. In this issue of Circulation Research , Hassel et al6 …