Models of flt-1 modulation of VEGF signal-negative modulation results in net positive effect on sprout formation. We favor a model of flt-1 action on sprout formation that results from flt-1 binding VEGF-A and preventing binding to flk-1 (see “Discussion” for details). This could occur in several ways. (A) VEGF-Amay be deposited in a gradient between the producing tissue and the target vessel, and this unmodified gradient is not conducive to sprout formation in the absence of flt-1. (B) sflt-1 may be secreted and form a counter-gradient that modifies and steepens the VEGF-A gradient, leading to increased sprout formation. (C) mflt-1 and/or sflt-1 may locally decrease the availability of VEGF-A, leading to increased sprout formation.