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The role of NOTCH agonist and inhibitor on CC fibroblasts

ABSTRACT: Fibroblasts are the most abundant cell population in human corpus cavernosum. Previously, they are regarded as static and homogeneous cells, however, recent study reported fibroblasts are a dynamic and heterogeneous cell population. An article published in ‘Science’ discovered that CC fibroblasts act as key blood flow regulators, shifting the balance between vasodilators and the vasoconstrictor norepinephrine toward vasodilation. Notch signaling serves as a central hub coordinating fibroblast turnover, norepinephrine sensitivity, and, ultimately, the erectile process. We treated CC fibroblasts with NOTCH agonist and inhibitor and performed transcriptome to find out the mechanism of Notch signaling on CC fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272522 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Purpose: Molecular mechanisms of penile corpus cavernosum aging and male age-related erectile dysfunction (ED) remain unclear. Here we profiled young and old rat penile corpus cavernousm by single-cell RNA sequencing (scRNA-seq). Methods:To map the single-cell transcriptomic landscape of penile corpus cavernosum during aging, we performed uniform manifold approximation and projection (UMAP), differential gene expression analysis (DGEs), pseudotime analysis and single-cell entropy algorithm to dissect cellular composition and transcriptional heterogeneity. For validation analysis, we further performed immunofluorescence studies on key molecules involved during penile corpus cavernosum aging. Results: After stringent filtering,transcriptomes of 14,879 single cells (8,557 young and 6,322 old) derived from penile corpus cavernosum of 5 young (3 months) and 5 old (23 months) rats were analyzed subsequently. Clustering analysis of cell-type specific gene expression identified 19 cell types, such as smooth muscle cells, endothelial cells, fibroblasts,myofibroblasts and immune cells.Transcriptomic analyses revealed that transcriptional alterations across all cell types exhibited distinct properties rather than universally consistent. DGEs analysis demonstrated that genes related to extracellular matrix organization were highly expressed. Among these cell types, fibroblasts showed apparent heterogeneities. By performing pseudotime and single-cell entropy analysis on fibroblasts, we observed the age-associated decrease of entropy, and aged fibroblasts were found to adopt senescent secretory phenotype, as evidenced by the high expression of genes associated with the senescence-associated secretory phenotype (SASP). Since eliminating senescent cells or SASP were demonstrated to improve health and life span, we further investigated the distinct senescence-related gene expression signatures across all cell types during aging. Conclusions: We plotted a cellular atlas of penile corpus cavernosum, and revealed the molecular alterations of aging cells, especially fibroblasts. Our work will deepen the understanding of the heterogeneity among certain cell types during penile corpus cavernosum aging and provide novel entry points for the age-associated ED treatment.

Project description:Background: Erectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood. Objective: This study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75. Materials and Methods: Erectile function was assessed by determining the intracavernous pressure/ mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry. Results: The SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum. Conclusion: These findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.

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The role of NOTCH agonist and inhibitor on CC fibroblasts

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