Macrophage-derived IL-1β drives endothelial-mesenchymal transition in diabetes mellitus erectile dysfunction

Abstract

Diabetes mellitus erectile dysfunction (DMED) is frequently accompanied by corpus cavernosum (CC) fibrosis and endothelial dysfunction; however, the cellular drivers and molecular mechanisms underlying these pathological changes remain incompletely understood. Endothelial-to-mesenchymal transition (EndMT), a phenotypic conversion in which endothelial cells lose endothelial characteristics and acquire mesenchymal features, has emerged as a key contributor to tissue fibrosis under inflammatory and metabolic stress conditions. Macrophages (Mφ), the predominant immune cell population in CC tissue in diabetes, are major sources of pro-inflammatory cytokines and may promote fibrosis by driving EndMT. This study investigated the role and mechanisms of Mφ in CC fibrosis during DMED and explored potential therapeutic targets. In a streptozotocin-induced DMED rat model, erectile function was significantly impaired, as evidenced by a marked reduction in the maximum intracavernous pressure-to-mean arterial pressure (ICP-to-MAP) ratio. This functional deterioration resulted from pronounced Mφ infiltration and enhanced fibrotic remodeling in CC. Pharmacological depletion of Mφ using clodronate liposomes significantly restored erectile function and increased the smooth muscle-to-collagen ratio. In vitro, co-culture of corpus cavernosum endothelial cells (CCEC) with Mφ under high-glucose (HG) conditions impaired endothelial tube formation and sprouting capacity, accelerated wound closure, and induced EndMT, characterized by downregulation of endothelial markers (CD34 and VE-cadherin) and upregulation of mesenchymal markers (Vimentin and α-SMA). RNA sequencing identified enrichment of interleukin-1 (IL-1)–related responses and Nuclear factor kappa B (NF-κB) signaling during EndMT. Further analyses demonstrated that HG stimulated Mφ to upregulate and secrete interleukin-1 beta (IL-1β), which in turn induced EndMT in CCEC accompanied by activation of NF-κB signaling, as evidenced by increased phosphorylation of p65 and IκBα. Pharmacological inhibition of the IL-1 receptor or NF-κB signaling effectively attenuated EndMT in vitro. Notably, in vivo administration of the IL-1 receptor antagonist Anakinra significantly improved erectile function and suppressed EndMT-associated molecular changes in DMED rats. Mφ-derived IL-1β promotes cavernosal fibrosis and erectile dysfunction in diabetes by inducing EndMT through activation of the NF-κB pathway. Targeting the IL-1β/NF-κB/EndMT axis represents a promising therapeutic strategy for the treatment of DMED.