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Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions.

ABSTRACT: With the diverse origin of neointimal cells, previous studies have documented differences of neointimal cell lineage composition across models, but the animal-to-animal difference has not attracted much attention, although the cellular heterogeneity may impact neointimal growth and its response to therapeutic interventions.R26R(+);Myh11-CreER(+), and R26R(+);Scl-CreER(+) mice were used to attach LacZ tags to the preexisting smooth muscle cells (SMCs) and endothelial cells (ECs), respectively. Neointimal lesions were created via complete ligation of the common carotid artery (CCA) and transluminal injury to the femoral artery (FA).LacZ-tagged SMCs were physically relocated from media to neointima and changed to a dedifferentiated phenotype in both CCA and FA lesions. The content of SMCs in the neointimal tissue, however, varied widely among specimens, ranging from 5 to 70% and 0 to 85%, with an average at low levels of 27% and 29% in CCA (n = 15) and FA (n = 15) lesions, respectively. Bone marrow cells, although able to home to the injured arteries, did not differentiate fully into SMCs after either type of injury. Preexisting ECs were located in the subendothelial region and produced mesenchymal marker ?-actin, indicating endothelial-mesenchymal transition (EndoMT); however, EC-derived cells represented only 7% and 3% of the total neointimal cell pool of CCA (n = 7) and FA (n = 7) lesions, respectively. ECs located on the luminal surface exhibited little evidence of EndoMT.Neointimal hyperplasia proceeds with a wide range of variation in its cellular composition between individual lesions. Relative to ECs, SMCs are major contributors to the lesion-to-lesion heterogeneity in neointimal cell lineage composition.

SUBMITTER: Yang P

PROVIDER: S-EPMC4707076 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions.

Yang Pu P Hong Michael S MS Fu Chunhua C Schmit Bradley M BM Su Yunchao Y Berceli Scott A SA Jiang Zhihua Z

Surgery 20150919 2

<h4>Background</h4>With the diverse origin of neointimal cells, previous studies have documented differences of neointimal cell lineage composition across models, but the animal-to-animal difference has not attracted much attention, although the cellular heterogeneity may impact neointimal growth and its response to therapeutic interventions.<h4>Methods</h4>R26R(+);Myh11-CreER(+), and R26R(+);Scl-CreER(+) mice were used to attach LacZ tags to the preexisting smooth muscle cells (SMCs) and endoth ...[more]

PMID: 26387788

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Project description:Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-?1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle ? actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

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Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions.

Publications

Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions.

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