CCN5 suppresses injury-induced vascular restenosis by inhibiting smooth muscle cell proliferation and facilitating endothelial repair via thymosin β4 and Cd9 pathway.

Summary

CCN5 emerged as a dual-acting regulator of restenosis: it restrains VSMC proliferation and accelerates endothelial repair via Tβ4/Ac-SDKP and Cd9 pathways. A CCN5 recombinant protein–coated stent increased endothelial coverage and reduced neointimal formation in a porcine model, highlighting a pro-healing anti-ISR strategy.

Key Findings

• Plasma CCN5 levels were reduced in ISR patients and correlated with restenosis severity; VSMC CCN5 was downregulated in injured/stented segments while regenerating ECs showed increased CCN5.
• Cell-specific CCN5 deletion aggravated neointimal hyperplasia; gain-of-function attenuated it.
• Mechanistically, EC-CCN5 interacted with thymosin β4 leading to Ac-SDKP–mediated repair and engaged Cd9 to promote endothelial repair; CCN5rp-coated stents increased EC coverage and reduced neointimal growth in porcine arteries.

Clinical Implications

If translated clinically, CCN5-based coatings could lower ISR without impairing healing, potentially shortening DAPT needs and improving long-term patency after PCI.

Limitations

• Preclinical nature; clinical efficacy and safety of CCN5-coated stents require human trials.
• Quantitative sample sizes per experiment are not detailed in the abstract.

Future Directions

First-in-human studies of CCN5-coated stents focusing on endothelialization, ISR, thrombosis, and DAPT duration; exploration of CCN5 agonism or delivery systems.