Model proposing a mechanism for differential Flt-1 isoform activity in Flk signaling and branching morphogenesis. We propose a model in which Flt-1 secreted from endothelial cells modulates a VEGF-A gradient (greenish blue) to affect ligand availability based on the heterogenous expression of both Flt-1 isoforms in developing vessels. (A) In WT vessels, both mFlt-1 and sFlt-1 act as ligand sinks to modulate the amplitude of the VEGF signal to endothelial cells. The ability of sFlt-1 to be secreted leads to the modulation of pFlk signaling in neighboring cells as well. (B) In the absence of Flt-1, the VEGF-A gradient is not modulated either quantitatively or qualitatively, which leads to excess and more uniform pFlk signaling and aberrant proliferation and branching. (C) Expression of an mFlt-1 transgene reduces overall levels of pFlk signaling, but the pattern of pFlk activation remains more homogeneous because the mFlt-1 effects are cell autonomous and do not extend to neighboring cells. Thus, proliferation but not branching is rescued. (D) Expression of an sFlt-1 transgene also reduces overall levels of Flk-1 activation and modulates signal amplitude to rescue proliferation, but the ability of sFlt-1 to be secreted allows it to modulate ligand availability to nearby cells and thus restores more of the heterogeneity of pFlk staining and rescue branching. Green arrows denote sFlt-1 protein, green cups denote mFlt-1 protein, and red dots denote pFlk expression.