Abstract
Dysfunctional angiogenesis is implicated in several pathologies that affect tens of millions of patients in the U.S.
alone. A lack of healthy vascularization can result in lethal complications, including tissue death and limb
amputation, and current solutions fail to promote stable vasculature. Therefore, there is a demand for strategies
that can support healthy vascularization throughout the angiogenic process. As high-level regulators of
angiogenesis and healing, macrophages are an attractive target for pro-angiogenic cell therapies. Intensely
responsive to environmental stimuli, macrophages have been shown to exhibit a pro-inflammatory (M1)
phenotype in early healing, then a less-inflammatory M2 phenotype dominates later stages. Although the roles
of macrophage phenotypes in angiogenesis are poorly understood, studies suggest that M1 macrophages
induce sprouting of new blood vessels, then M2 macrophages promote stabilization. In vivo, the M2 population
can derive from circulating monocytes, or from the phenotypic switching of pre-existing M1 macrophages, but it
is unknown to what extent each group is present or what they contribute to angiogenesis. We have previously
shown that IL-4 causes M1-activated macrophages to switch to an M2 phenotype with some increased
angiogenic functions, compared to IL-4-treated M0 macrophages. We hypothesize that M1-derived M2
macrophages are a unique phenotype essential to angiogenesis, and that promoting the M1-to-M2 switch with
biomaterials will enhance angiogenesis in vivo. Aim 1 will thoroughly investigate the differences between M0-
derived and M1-derived M2 macrophages in vivo using next-generation sequencing, producing the unique gene
signatures and functional phenotypes of each group. In Aim 2, PLGA microparticles will be loaded with the M2-
promoting drug simvastatin, then co-cultured with M0 or M1 macrophages to facilitate phagocytosis. The
macrophages will then be injected into a murine model of wound healing, and as the microparticles degrade and
release simvastatin, the drug will promote M2 polarization intracellularly. It is expected that the group undergoing
the M1-to-M2 transition will augment angiogenesis. This study will increase our understanding of the roles of
macrophage phenotype during angiogenesis, and will result in a translational pro-angiogenic biomaterials-based
cell therapy.