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S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation.

ABSTRACT: INTRODUCTION:Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. METHODS AND RESULTS:The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1? expressions were obviously increased, and SDF-1? levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1?/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and ?-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1? expressions in VSMCs by activating PI3K/AKT and NF-?B, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells' differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and ?-SMA. CONCLUSIONS:S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1? by activating PI3K/AKT and NF-?B.

SUBMITTER: Wu Y

PROVIDER: S-EPMC6757428 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation.

Wu Yan Y Liu Xin X Guo Ling-Yun LY Zhang Lei L Zheng Fei F Li Shan S Li Xing-Yuan XY Yuan Ye Y Liu Yu Y Yan Yu-Wen YW Chen Shi-You SY Wang Jia-Ning JN Zhang Jin-Xuan JX Tang Jun-Ming JM

Stem cell research & therapy 20190923 1

<h4>Introduction</h4>Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown.<h4>Methods and results</h4>The neointimal formation model in rats was establish ...[more]

PMID: 31547879

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Project description:Injury-induced stenosis is a serious vascular complication. We previously reported that p38? (MAPK14), a redox-regulated p38MAPK family member was a negative regulator of the VSMC contractile phenotype in vitro. Here we evaluated the function of VSMC-MAPK14 in vivo in injury-induced neointima hyperplasia and the underlying mechanism using an inducible SMC-MAPK14 knockout mouse line (iSMC-MAPK14-/-). We show that MAPK14 expression and activity were induced in VSMCs after carotid artery ligation injury in mice and ex vivo cultured human saphenous veins. While the vasculature from iSMC-MAPK14-/- mice was indistinguishable from wildtype littermate controls at baseline, these mice exhibited reduced neointima formation following carotid artery ligation injury. Concomitantly, there was an increased VSMC contractile protein expression in the injured vessels and a decrease in proliferating cells. Blockade of MAPK14 through a selective inhibitor suppressed, while activation of MAPK14 by forced expression of an upstream MAPK14 kinase promoted VSMC proliferation in cultured VSMCs. Genome wide RNA array combined with VSMC lineage tracing studies uncovered that vascular injury evoked robust inflammatory responses including the activation of proinflammatory gene expression and accumulation of CD45 positive inflammatory cells, which were attenuated in iSMC-MAPK14-/- mice. Using multiple pharmacological and molecular approaches to manipulate MAPK14 pathway, we further confirmed the critical role of MAPK14 in activating proinflammatory gene expression in cultured VSMCs, which occurs in a p65/NFkB-dependent pathway. Finally, we found that NOX4 contributes to MAPK14 suppression of the VSMC contractile phenotype. Our results revealed that VSMC-MAPK14 is required for injury-induced neointima formation, likely through suppressing VSMC differentiation and promoting VSMC proliferation and inflammation. Our study will provide mechanistic insights into therapeutic strategies for mitigation of vascular stenosis.

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.

Dataset Information

S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation.

Publications

S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation.

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