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

Area of Science:

• Urology
• Immunology
• Vascular Biology

Background:

• Arteriogenic erectile dysfunction (AED) stems from poor arterial blood flow into the corpus cavernosum, with complex causes and limited treatments.
• The role of electrical stimulation (ES) in AED's pathophysiology, particularly its impact on the immune microenvironment and smooth muscle cells, is largely unknown.

Purpose of the Study:

• To investigate if ES can improve AED by modulating the local immune microenvironment and preventing pathological changes in cavernous smooth muscle cells (SMCs).
• To explore the molecular mechanisms underlying ES's therapeutic effects in an AED rat model.

Main Methods:

• An AED rat model was created using cuff-induced endothelial injury and a high-fat diet.
• Erectile function was assessed via intracavernous pressure measurement and infrared thermography.
• Molecular analyses included immunohistochemistry, co-immunoprecipitation, and an in vitro co-culture system of macrophages and corpus cavernosum smooth muscle cells (CCSMCs).

Main Results:

• ES treatment significantly restored erectile function in AED rats.
• ES induced macrophage polarization towards an anti-inflammatory M2 phenotype, linked to increased cylindromatosis (CYLD) and reduced CX3CL1.
• M2-derived Th2 cytokines promoted P300/Myocardin (Myocd) acetylation in SMCs, inhibiting their synthetic phenotype transition and preventing adverse vascular remodeling.

Conclusions:

• Electrical stimulation ameliorates AED by orchestrating crosstalk between macrophages and SMCs.
• ES promotes M2 macrophage polarization, which inhibits detrimental CCSMC phenotypic switching via CYLD upregulation and CX3CL1 reduction, thus preserving vascular integrity and erectile function.