The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis

Sprouting angiogenesis is critical to blood vessel formation, but the cellular and molecular controls of this process are poorly understood. We used time-lapse imaging of green fluorescent protein (GFP)-expressing vessels derived from stem cells to analyze dynamic aspects of vascular sprout formation and to determine how the vascular endothelial growth factor (VEGF) receptor fit-1 affects sprouting. Surprisingly, loss of fit-1 led to decreased sprout formation and migration, which resulted in reduced vascular branching. This phenotype was also seen in vivo, as fit-1(-/-) embryos had defective sprouting from the dorsal aorta. We previously showed that loss of fit-1 increases the rate of endothelial cell division. However, the timing of division versus morphogenetic effects suggested that these phenotypes were not causally linked, and in fact mitoses were prevalent in the sprout field of both wild-type and fit-1(-/-)mutant vessels. Rather, rescue of the branching defect by a soluble fit-1(-/-) (sflt-1) transgene supports a model whereby fit-1 normally positively regulates sprout formation by production of sfit-1, a soluble form of the receptor that antagonizes VEGF signaling. Thus precise levels of bioactive VEGF-A and perhaps spatial localization of the VEGF signal are likely modulated by fit-1 to ensure proper sprout formation during blood vessel formation. (C) 2004 by The American Society of Hematology.