EphA2 signaling mechanisms in smooth muscle proliferation and migration in atherosclerosis

Project: Research


  • Matthew Lawson Scott (PI)


The Eph family of receptor tyrosine kinases, the largest in the mammalian genome, and their ephrin ligands critically influence inflammation in a variety of pathologies. Our work provided the first description of EphA2 expression in multiple cell types in the atherosclerotic plaque, and we recently demonstrated that EphA2 deletion reduces plaque formation associated with diminished plaque inflammation. Surprisingly, EphA2 deletion reduced advanced atherosclerotic disease progression and diminished plaque smooth muscle cell (SMC) content. Contractile-to-synthetic phenotypic modulation drives SMC accumulation during plaque development, and SMCs show enhanced EphA2 expression during phenotypic modulation both in vitro and in vivo.We demonstrated a critical role for EphA2 expression in SMC mitogenic signaling (ERK1/2, AKT) and proliferation both in vitro and in plaques in vivo. While EphA2 ligation by ephrinA1 elicits multiple aspects of EphA2's atherogenic proinflammatory responses, our preliminary data show that EphA2 ligation reduces SMC proliferation. Conversely, EphA2 can also signal in a ligand-independent state, which promotes cell proliferation and migration in cancer models, and we observed an increase in EphA2 ligand-independent signaling (Ser897 phosphorylation) during SMC proliferation in vitro and at sites of SMC phenotypic modulation in vivo. However, the mechanisms regulating EphA2's differential ligand-dependent and ligand-independent mitogenic signaling remain virtually unexplored. Therefore, we hypothesize that EphA2 ligand-independent signaling promotes smooth muscle proliferation in the atherosclerotic plaque. To test this hypothesis, we will determine the mechanisms by which EphA2 signaling affects SMC phenotype and function (Aim 1), and we will assess the role of EphA2 cell-type specific expression and signaling in atherosclerotic fibroproliferative remodeling using novel EphA2 conditional knockouts and inhibitors of EphA2 ligation and kinase activity (Aim 2). This work will provide valuable insight into potential mechanisms of EphA2-regulated SMC function and further provide insight into the effect that differential regulation of EphA2-signaling (ligand-dependent/independent) has on plaque formation and progression. Finally, this work will provide a crucial basis upon which to critically evaluate the potential of EphA2 as a therapeutic target within human disease.
Award amount$128,080.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35220022
Effective start/end date01/01/202012/31/2021