Electrical stimulation improves arteriogenic erectile dysfunction by modulating CYLD-mediated macrophage-smooth muscle cell crosstalk.

Arteriogenic erectile dysfunction (AED) results from insufficient arterial filling of the corpus cavernosum. Its complex pathophysiology is poorly understood, and current treatments have limitations. While electrical stimulation (ES) has been widely applied clinically for male diseases, its therapeutic targets in AED remain unexplored. This study aimed to investigate the hypothesis that ES ameliorates AED by improving the local immune microenvironment and inhibiting the pathological phenotypic transformation of cavernous smooth muscle cells (SMCs). An AED rat model was established via cuff-induced endothelial injury and a high-fat diet. Erectile function, histology, and molecular mechanisms were assessed using intracavernous pressure measurement, infrared thermography, immunohistochemistry, co-immunoprecipitation, and an in vitro macrophage-corpus cavernosum smooth muscle cells (CCSMCs) co-culture system. Our findings demonstrate that ES treatment significantly improved erectile function in the AED rat model. We discovered that macrophages were polarized towards the anti-inflammatory M2 phenotype following ES treatment. This polarization was directly associated with the upregulation of cylindromatosis (CYLD) and the subsequent inhibition of CX3CL1 release. Concurrently, Th2 cytokines released from these M2 macrophages further enhanced P300/Myocardin (Myocd) acetylation in SMCs, which critically inhibited their transformation towards a synthetic phenotype and prevented adverse vascular remodeling. This study demonstrates that crosstalk between macrophages and SMCs is an essential mechanism in ES-treated AED. We verify that ES-induced M2 macrophage polarization inhibits the detrimental phenotypic switching of CCSMCs, thereby preserving vascular integrity and improving erectile function. This process is pivotally regulated by the upregulation of CYLD and reduction of CX3CL1.