Induction of Angiogenesis in Microfluidics by using Prolyl Hydroxylase Inhibitor and Sphingosine I-Phosphate

Abstract

Prolyl hydroxylase inhibitors (PHis) and sphigosine 1-phosphate (S1P) are shown to induce capillary sprouting in a co-culture microfluidic platform. Combining both factors further enhances the formation of complex tubular networks with lumina. The pro-angiogenic effects are only observed in co-culture with fibroblasts and are explained by the generation of mutually stimulating factors between endothelia (EC) and fibroblasts. S1P induced migration has been shown to be S1P receptor 1 (S1P1) dependent. The downregulation of either VEGF or S1P1 attenuates capillary sprouting and changes the sprouting morphologies. MCP-1 is mainly secreted by fibroblasts, but only in the presence of ECs or EC-conditioned medium, creating an angiogenic effect on sprouting. Blocking antibodies against MCP-1 inhibit the sprouting response. These observations not only confirm the importance of EC-fibroblast crosstalk in angiogenesis but also suggest that the combination of PHi and S1P enhances this synergy and thus might be of therapeutic value for tissue regeneration.