ETS Homologous Factor Drives Endothelial Dysfunction in Diabetes-Related Erectile Dysfunction via Regulating SPRY1 Ubiquitination and NOS3 Autophagy.

Abstract

Purpose: Diabetes mellitus (DM)-related erectile dysfunction (DMED), a prevalent complication of diabetes, is closely associated with endothelial dysfunction. This study investigated the role of E26 transformation-specific homologous factor (Ehf) in mediating endothelial dysfunction in DMED and explored its downstream molecular mechanisms.

Materials and methods: Rat corpus cavernosum endothelial cells (CCECs) were cultured under high glucose (HG) conditions to simulate a diabetic environment in vitro. Endothelial function was assessed through functional assays, including tube formation and Evans blue permeability tests, following overexpression or knockdown of Ehf, Spry1, or Nos3. Co-immunoprecipitation, ChIP, and dual-luciferase reporter assays were utilized to evaluate molecular interactions and regulatory mechanisms.

Results: Ehf expression was significantly elevated in HG-treated CCECs and impaired endothelial function through two distinct mechanisms. First, Ehf stabilized the angiogenesis inhibitor SPRY1 by promoting its acetylation at lysine 300 via ESCO1, thereby reducing its ubiquitination by NEDD4. Second, Ehf induced NOS3 degradation through autophagy by upregulating ATG5 and enhancing the NOS3-NBR1 interaction. These dual mechanisms suppressed angiogenesis and increased vascular permeability, contributing to endothelial dysfunction in DMED.

Conclusions: Ehf exacerbates DMED by disrupting penile endothelial function through SPRY1 stabilization and NOS3 degradation. These findings present novel molecular targets for potential therapeutic strategies in DMED.