Project Summary
The ability to restore the microvasculature and improve perfusion, by expanding the population of endothelial
cells in vivo, would be a major advancement in cardiovascular medicine and create a novel therapeutic approach
to cardiovascular disease. The proposed studies, aimed at identifying the role of O-GlcNAcylation in
transdifferentiation and epigenetic plasticity, may reveal a novel mechanism of neovascularization and uncover
new avenues for therapeutic angiogenesis and vasculogenesis (Carmeliet, 2005, Isner 1999).
Activation of inflammatory signaling pathways is required to drive fibroblasts to undergo angiogenic
transdifferentiation and become endothelial cells in vitro (Sayed, 2015). This process requires cell autonomous
innate immune signaling, which triggers global changes in expression and activity of epigenetic modifiers (Lee,
2012). The term “transflammation” describes the process by which innate immune signaling promotes
epigenetic plasticity and phenotypic fluidity. Recently, it has been shown that a glycolytic shift contributes to
transdifferentiation by increased nuclear acetyl-CoA for histone acetylation (Lai, 2019).
Although this glycolytic switch links metabolism to epigenetic modelling, the contribution of other metabolites to
epigenetic plasticity in neovascularization remains unexplored. Preliminary data indicate that O-GlcNAcylation,
and nutrient driven post-translational modification (PTM), is significantly elevated in angiogenic
transdifferentiation and neovascularization following hindlimb ischemia. This observation raises the exciting
possibility that O-GlcNAcylation links cell fate plasticity to metabolism in vascular transdifferentiation, and that
targeting this PTM may be a new therapeutic avenue in regenerative medicine.
The overarching hypothesis is that O-GlcNAcylation enhances neovascularization in recovery from ischemic
injury by facilitating cell fate plasticity, and that perturbations to O-GlcNAcylation through genetic and
pharmacologic manipulation will attenuate transdifferentiation and diminish neovascularization. The immediate
goal will be to determine if O-GlcNAcylation is required for angiogenic transdifferentiation and to identify targets
of O-GlcNAcylation contributing to epigenetic plasticity and cell fate fluidity in vascular transdifferentiation and
neovascularization. The proposed studies on O-GlcNAcylation in transdifferentiation will identify an
epigenetic mechanism for cellular plasticity and a novel therapeutic target to enhance endogenous
neovascularization for treatment of cardiovascular disease. The long term goal is to evaluate the
therapeutic efficacy of targeting O-GlcNAcylation to enhance vascular recovery in non-ischemic and ischemic
models of cardiovascular disease, such as heart failure and myocardial infarction.
Aim 1: Determine the role of O-GlcNAcylation in transdifferentiation and DNA accessibility in vitro.
Aim 2: Determine the role of O-GlcNAcylation in transdifferentiation and neovascularization in vivo.