Sequential delivery of vascular endothelial growth factor and sphingosine 1-phosphate for angiogenesis.

Angiogenesis is an organized series of events, beginning with vessel destabilization, followed by endothelial cell re-organization, and ending with vessel maturation. Vascular endothelial growth factor (VEGF) aids in vascular permeability and endothelial cell recruitment while sphingosine 1-phosphate (S1P) stimulates vascular stability. Accordingly, VEGF may inhibit vessel stabilization while S1P may inhibit endothelial cell recruitment. For this reason, we created a new externally-regulated delivery model that not only permits sustained release of bioactive factors, but also temporal separation of the delivery of growth factors. Using this model, sequential delivery of factors was first confirmed in vitro with associated endothelial cells responding in a dose dependent manner. Furthermore, using a modified murine Matrigel plug model, it is apparent that delivery strategies where VEGF presentation is temporally separated from S1P presentation not only led to greater recruitment of endothelial cells, but also higher maturation index of associated vessels.