Abstract
BackgroundThe origins of neointimal smooth muscle cells that arise following vascular injury remains controversial. Studies have suggested that these cells may arise from previously differentiated medial vascular smooth muscle cells, resident stem cells or blood born progenitors. In the current study we examined the contribution of the previously differentiated vascular smooth muscle cells to the neointima that forms following carotid artery ligation.MethodsWe utilized transgenic mice harboring a cre recombinase-dependent reporter gene (mTmG). These mice express membrane targeted tandem dimer Tomato (mTomato) prior to cre-mediated excision and membrane targeted EGFP (mEGFP) following excision. The mTmG mice were crossed with transgenic mice expressing either smooth muscle myosin heavy chain (Myh11) or smooth muscle α-actin (Acta2) driven tamoxifen regulated cre recombinase. Following treatment of adult mice with tamoxifen these mice express mEGFP exclusively in differentiated smooth muscle cells. Subsequently vascular injury was induced in the mice by carotid artery ligation and the contribution of mEGFP positive cells to the neointima determined.ResultsAnalysis of the cellular composition of the neointima that forms following injury revealed that mEGFP positive cells derived from either Mhy11 or Acta2 tagged medial vascular smooth muscle cells contribute to the majority of neointima formation (79 ± 17% and 81 ± 12%, respectively).ConclusionThese data demonstrate that the majority of the neointima that forms following carotid ligation is derived from previously differentiated medial vascular smooth muscle cells.
Highlights
The origins of neointimal smooth muscle cells that arise following vascular injury remains controversial
Using a genetic fate mapping approach with tamoxifen regulated smooth muscle-specific cre recombinase and a dual color cre-dependent reporter gene we unequivocally show that the neointimal SMCs that arise following carotid artery ligation are largely derived from the previously differentiated medial Vascular smooth muscle cells (VSMCs)
We speculate that one or more of these advantages of the mTmG reporter system and tamoxifen regulated cre transgenes used in our study may explain why we were able to detect membrane targeted EGFP (mEGFP) positive neointimal cells whereas they were not detected in a previous study [ 6]
Summary
The origins of neointimal smooth muscle cells that arise following vascular injury remains controversial. Studies have suggested that these cells may arise from previously differentiated medial vascular smooth muscle cells, resident stem cells or blood born progenitors. In the current study we examined the contribution of the previously differentiated vascular smooth muscle cells to the neointima that forms following carotid artery ligation
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