Abstract 1307: Proteomic and Metabolomic Analysis of Smooth Muscle Cells Derived from Adventitial Progenitors of Apolipoprotein E-deficient Mice
Background. We have recently demonstrated that stem cell antigen 1 positive (Sca-1+) progenitors exist in the vascular adventitia of apoE−/− mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis.
Methods and Results. We now demonstrate that this resident stem cell population migrates from the adventitia to the media during early atherosclerosis in chow-fed apoE−/− mice until they finally blend into the tissue in more complex lesions. Using a combined proteomic and metabolomic approach, we established that, unlike Sca-1+ progenitors from embryonic stem cells, Sca-1+ cells from the vasculature displayed protein profiles similar to mature aortic SMCs after incubation with PDGF in vitro. However, despite differentiation in a normolipidemic environment, they maintained functional alterations indicative of their apoE−/− origin under normoxic and hypoxic conditions as evidenced by differential expression of key proteins in glucose metabolism, accelerated glucose consumption, altered secretion of IL-6 and IL-18, elevated expression of insulin-growth factor binding proteins 3 and 6 and increased susceptibility to oxidative stress. Notably, reconstitution of IL-6 to levels measured in the conditioned medium of wildtype SMCs attenuated the elevated insulin-growth factor binding protein expression in apoE−/− SMCs and their vascular progenitors. Furthermore, a comparison of plasma metabolites and cytokine profiles from apoE−/− and E*3 Leiden transgenic mice confirmed an association of glucose metabolites rather than cholesterol levels with circulating IL-6 concentrations.
Conclusions. We provide evidence that Sca-1+ progenitors contribute to native atherosclerosis in apoE−/− mice, that apoE-deficiency alters progenitor cell behaviour and that inflammatory cytokines such as IL-6 may act as metabolic regulators in hyperlipidemic mice. While our data support the possibility of a physical incorporation of cells derived from resident progenitors in the vasculature, their overall similarity to mature apoE−/− SMCs, especially with respect to cytokine profiles, argues against a paracrine support or a limiting effect on inflammation.