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

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.

 

Comments:

The study you described investigates the impact of Myeloid-derived growth factor (MYDGF) on postinjury neointimal formation in rat carotid arteries following balloon injury. Neointimal formation, often associated with angioplasty, is characterized by abnormal vascular smooth muscle cell (VSMC) dedifferentiation. Here's a breakdown of the key findings and implications of this study:

### Key Findings:

1. **Decreased MYDGF Levels:** After balloon injury, both plasma MYDGF content and the levels of MYDGF in injured arteries were significantly reduced.

2. **MYDGF Application Inhibited Neointimal Formation:** Local application of exogenous MYDGF around the injured vessel during balloon injury reduced neointimal formation. This was evidenced by improvements in the endovascular diameter, hemodynamics, and reduced collagen deposition.

3. **Inhibition of VSMC Dedifferentiation:** MYDGF application inhibited VSMC dedifferentiation, which was confirmed by reversing the elevated levels of osteopontin (OPN) protein and increased levels of α-smooth muscle actin (α-SMA) in the carotid arteries.

4. **In Vitro Studies:** PDGF-BB stimulation induced VSMC proliferation, migration, and dedifferentiation. Pretreatment with MYDGF eliminated PDGF-BB-induced cell activities in a concentration-dependent manner.

5. **Molecular Mechanism:** MYDGF was found to bind with sphingosine-1-phosphate receptor 2 (S1PR2). Inhibition of S1PR2 or its downstream signaling pathways circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching. Specifically, the RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling pathway was involved.

### Implications and Significance:

1. **Therapeutic Potential:** The study suggests that MYDGF has therapeutic potential in preventing restenosis after angioplasty by inhibiting neointimal formation. By suppressing VSMC dedifferentiation, MYDGF could contribute to improved outcomes post-angioplasty procedures.

2. **Targeted Therapies:** Understanding the molecular pathways involved, especially the S1PR2-RhoA-G/F-actin-MRTF-A pathway, provides potential targets for drug development. Targeted therapies that modulate these pathways could be explored for preventing neointimal formation and improving the long-term success of angioplasty procedures.

3. **Cross Talk Between Bone Marrow and Vasculature:** The study highlights a connection between bone marrow-derived factors (MYDGF) and vascular health. This cross talk between bone marrow and vasculature could have broader implications in understanding cardiovascular diseases and developing novel treatments.

In summary, the findings of this study provide valuable insights into the mechanisms underlying neointimal formation and suggest MYDGF as a potential therapeutic agent to mitigate restenosis after angioplasty. The detailed understanding of the signaling pathways involved opens avenues for further research and targeted drug development in the field of vascular biology and cardiovascular medicine.