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Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling

Abstract

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 μg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50−200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

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Fig. 1: MYDGF decreases in rat plasma and carotid arteries after balloon injury.
Fig. 2: MYDGF alleviates abnormal blood flow velocity and histological remodeling of the carotid artery in rats with balloon injury.
Fig. 3: MYDGF inhibits cell proliferation and migration stimulated by PDGF-BB in A10 VSMCs.
Fig. 4: MYDGF maintains the differentiated phenotype of PDGF-BB-treated A10 VSMCs.
Fig. 5: Effect of MYDGF on the S1PR2-Rho-ROCK-F/G-actin-MRTF-A signaling pathway.
Fig. 6: Blockade of S1PR2-Rho-ROCK signaling abolishes the inhibitory effect of MYDGF on cell proliferation and migration induced by PDGF-BB in A10 VSMCs.
Fig. 7: Blockade of the S1PR2-Rho-ROCK signaling pathway abolishes maintenance of the A10 VSMC differentiation phenotype by MYDGF.
Fig. 8: Schematic diagram depicting the molecular mechanism of MYDGF in maintaining the smooth muscle cell differentiation phenotype.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82170431, 81870259, 81903608).

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SY designed research; SY, TTZ, JYT, CYM, YC, Yu Zhao, QL, LYJ, Zhengkai Wang, Zhiqi Wang, WYJ, MF, SFC, Xue Li and JR and performed research; SY analyzed data; SY wrote the paper. Yan Zhang, HWL, Yixiu Zhao helped perform the analysis with constructive discussions. Yan Zhang and Xue Liu helped polish the article.

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Correspondence to Yan Zhang or Xue Liu.

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Yang, S., Li, Hw., Tian, Jy. et al. Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling. Acta Pharmacol Sin 45, 98–111 (2024). https://doi.org/10.1038/s41401-023-01155-x

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