Extracorporeal cardiac shock wave therapy modulates post-infarction neovascularization via CAC-mediated pro-angiogenic effects and modulation of the S100A4/CSF2/FOXO1 protein network

Ischemic heart disease (IHD) remains the leading cause of mortality worldwide, and the long-term benefits conferred by revascularization are limited. Cardiac shock wave therapy (CSWT) can promote neovascularization and attenuate myocardial injury, and has been applied in the treatment of IHD; its mechanism may involve Circulating Angiogenic cells (CACs) and their key proteins. This study aimed to explore the potential mechanism by which CSWT exerts effects on angiogenesis and attenuates structural damage following Acute Myocardial Infarction (AMI). Using in vivo and in vitro experiments combined with Olink proteomics, three core regulatory proteins involved in angiogenesis, namely S100A4, CSF2, and FOXO1, were screened. In vitro , optimized CSWT enhanced the migration and tube formation of rat bone marrow-derived CACs, as well as the expression of pro-angiogenic factors such as VEGF and HGF. In vivo , CSWT after AMI reduced infarct size, elevated the levels of CACs (CD34/CD133) and vascular markers (CD31/ α -SMA), and modulated 18 differentially expressed proteins. Key regulatory factors S100A4, CSF2, and FOXO1 were identified by Olink proteomics. The expression levels of these proteins were verified by dual qPCR experiments in vitro and in vivo . The results reveal that CSWT modulates the S100A4/CSF2/FOXO1 network and activates CACs in AMI, suggesting a mechanistic basis for further translational evaluation of CSWT as a potential adjuvant therapy for IHD.