CCN5 suppresses injury-induced vascular restenosis by inhibiting smooth muscle cell proliferation and facilitating endothelial repair via thymosin β4 and Cd9 pathway.
This study investigated the role of CCN5, a matricellular protein, in preventing vascular restenosis after stent implantation (in-stent restenosis, ISR). Using RNA sequencing of stent-implanted porcine coronary arteries and single-cell RNA sequencing of mouse femoral artery injury models, the researchers found that CCN5 expression was reduced in vascular smooth muscle cells (VSMCs) following injury but elevated in regenerating endothelial cells (ECs). In ISR patients, plasma CCN5 levels were significantly lower and correlated inversely with restenosis severity. Using cell-type-specific loss- and gain-of-function mouse models, the study found that EC- and VSMC-specific deletion of CCN5 worsened neointimal hyperplasia, while CCN5 overexpression was protective. Mechanistically, CCN5 was found to interact with thymosin β4 (Tβ4) in ECs, promoting endothelial repair via the cleavage product Ac-SDKP, and also interacted with CD9 to support EC recovery. A CCN5 recombinant protein (CCN5rp)-coated stent deployed in a porcine model significantly increased endothelial strut coverage and reduced neointimal formation. Limitations include the translational gap between animal models and humans, and the observational nature of the patient plasma data.
Why this grade: The study includes a human correlative component (plasma CCN5 in ISR patients) but the mechanistic and interventional findings are derived from animal and in vitro models, limiting direct human evidence of efficacy.
Background and aims Members of the CCN matricellular protein family are crucial in various biological processes. This study aimed to characterize vascular cell-specific effects of CCN5 on neointimal formation and its role in preventing in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). Methods Stent-implanted porcine coronary artery RNA-seq and mouse injury-induced femoral artery neointima single-cell RNA sequencing were performed. Plasma CCN5 levels were measured by enzyme-linked immunosorbent assay. Endothelial cell (EC)- and vascular smooth muscle cell (VSMC)-specific CCN5 loss-of-function and gain-of-function mice were generated. Mass spectrometry and co-immunoprecipitation were conducted to identify CCN5 interacting proteins. Additionally, CCN5 recombinant protein (CCN5rp)-coated stents were deployed to evaluate its anti-ISR effects in a porcine model. Results Plasma CCN5 levels were significantly reduced and correlated closely with the degree of restenosis in ISR patients. CCN5 expression was significantly decreased in VSMCs of stent-implanted porcine coronary segments and injured mouse femoral arteries, especially in synthetic VSMCs. In contrast, elevated CCN5 expression was observed in regenerating ECs of injured vessels. Endothelial cell- and VSMC-specific CCN5 deletion mice exhibited exacerbation of injury-induced neointimal hyperplasia, while CCN5 gain-of-function alleviated neointimal formation. Mechanistic studies identified thymosin β4 (Tβ4) as a CCN5 interacting protein in ECs and EC-CCN5 promoted injury repair through Tβ4 cleavage product Ac-SDKP. Also, CCN5rp promoted EC repair to suppress neointimal hyperplasia via interaction with Cd9 extracellular domain. Moreover, implantation with CCN5rp-coated stent significantly increased stent strut coverage with ECs, which suppressed neointimal formation and ultimately alleviated ISR. Conclusions CCN5 exerts a dual protective effect on ISR by inhibiting VSMC proliferation and facilitating EC repair. CCN5rp-coated stent might be promising in the prevention of ISR after PCI.
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