Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth

Lauren S. Sefcik, Caren E. Petrie Aronin, Anthony O. Awojoodu, Soo J. Shin, Feilim Mac Gabhann, Timothy L. MacDonald, Brian R. Wamhoff, Kevin R. Lynch, Shayn M. Peirce, Edward A. Botchwey

Research output: Contribution to journalArticlepeer-review


Proper spatial and temporal regulation of microvascular remodeling is critical to the formation of functional vascular networks, spanning the various arterial, venous, capillary, and collateral vessel systems. Recently, our group has demonstrated that sustained release of sphingosine 1-phosphate (S1P) from biodegradable polymers promotes microvascular network growth and arteriolar expansion. In this study, we employed S1P receptor-specific compounds to activate and antagonize different combinations of S1P receptors to elucidate those receptors most critical for promotion of pharmacologically induced microvascular network growth. We show that S1P1 and S1P3 receptors act synergistically to enhance functional network formation via increased functional length density, arteriolar diameter expansion, and increased vascular branching in the dorsal skinfold window chamber model. FTY720, a potent activator of S1P1 and S1P3, promoted a 107% and 153% increase in length density 3 and 7 days after implantation, respectively. It also increased arteriolar diameters by 60% and 85% 3 and 7 days after implantation. FTY720-stimulated branching in venules significantly more than unloaded poly(D, L-lactic-co-glycolic acid). When implanted on the mouse spinotrapezius muscle, FTY720 stimulated an arteriogenic response characterized by increased tortuosity and collateralization of branching microvascular networks. Our results demonstrate the effectiveness of S1P1 and S1P3 receptor-selective agonists (such as FTY720) in promoting microvascular growth for tissue engineering applications.

Original languageEnglish (US)
Pages (from-to)617-629
Number of pages13
JournalTissue Engineering - Part A
Issue number5-6
StatePublished - Mar 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomedical Engineering
  • Biomaterials


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