Intimal medial thickening (IMT) and vascular remodelling are hallmarks of arteriosclerotic disease. The origin of neointimal cells and the signalling molecules that direct their fate and function is controversial. Here, we demonstrate that Hedgehog (Hh) responsive S100β+/Sca1+ perivascular stem cells substantially contribute to IMT within carotid arteries of transgenic mice following ligation-induced injury in vivo. Genetic lineage tracing analysis using S100β-eGFP/Cre/ERT2 transgenic mice to mark resident vascular stem cells before injury demonstrated that Hh responsive S100β+/Sca1+ cells substantially contribute to IMT, an effect significantly attenuated following treatment with the Hh smoothened inhibitor, cylopamine. In vitro, recombinant SHh (rSHh) treatment of multipotent S100β+/Sca1+ resident stem cells increased target gene Gli expression, decreased telomerase activity, and promoted myogenic differentiation and cell growth; effects significantly attenuated following Hh inhibition. These findings suggest that perivascular S100β+/Sca1+ stem cells are a major source of neointimal cells contributing to IMT and suggest that this cohort may be a relevant therapeutic target to prevent arteriosclerosis.
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