Gene expression profile comparison in the penile tissue of diabetes and cavernous nerve injury-induced erectile dysfunction rat model

Abstract

Purpose: To investigate the effects of cavernous nerve injury (CNI) on gene expression profiles in the cavernosal tissue of a CNI-induced erectile dysfunction (ED) model and to provide a basis for future investigations to discover potential target genes for ED treatment.

Materials and methods: Young adult rats were divided randomly into 2 groups: sham operation and bilateral CN resection. At 12 weeks after CNI we measured erectile responses and performed microarray experiments and gene set enrichment analysis to reveal gene signatures that were enriched in the CNI-induced ED model. Alterations in gene signatures were compared with those in the diabetes-induced ED model. The diabetic-induced ED data is taken from GSE2457.

Results: The mean ratio of intracavernosal pressure/blood pressure for the CNI group (0.54±0.4 cmH2O) was significantly lower than that in the sham operation group (0.73±0.8 cmH2O, p<0.05). Supervised and unsupervised clustering analysis showed that the diabetes- and CNI-induced ED cavernous tissues had different gene expression profiles from normal cavernous tissues. We identified 46 genes that were upregulated and 77 genes that were downregulated in both the CNI- and diabetes-induced ED models.

Conclusions: Our genome-wide and computational studies provide the groundwork for understanding complex mechanisms and molecular signature changes in ED.

Keywords: Erectile dysfunction; Gene expression; Microarray analysis; Peripheral nerve injuries.

Fig. 1. Representative records of data and intracavernosal pressure/ blood pressure (ICP/BP) from electric field stimulation at 12 weeks after cavernous nerve injury (CNI). Representative time course of changes in ICP for sham operation group rats (A), cavernous nerve (CN) crushing injury group rats (B), and summary of all in vivo data (C). In vivo experiments were performed 12 weeks after CNI in rats. ^*p-value<0.05, response significantly different compared with sham operation group.

Fig. 2. Different gene expression patterns between normal and diabetes- or cavernous nerve injury (CNI)-induced erectile dysfunction (ED) penile tissues. (A) Unsupervised hierarchical clustering of gene expression profile distinguishes the CNI-induced ED model from (B) the diabetes-induced ED model. (C, D) Principal component analysis (PCA) plots for the CNI-induced and diabetes-induced model data. The sum of % variance is shown for each PCA plot. The diabetic-induced ED (DIED) data is taken from GSE2457 [10]. SON, sham operation normal tissue; NCT, normal cavernous tissue.

Fig. 3. Enrichment plot of ANATOMICAL_STRUCTURE_DEVELOPMENT gene signatures. The square box indicates the leading edge subset and the heat map presents 39 genes of the leading edge subset. SON, sham operation normal tissue; CNI_ED, cavernous nerve injury-induced erectile dysfunction; FDR, false discovery rate is the estimated probability that a gene set with a given NES represents a false positive finding; ES, enrichment score; NES, normalized enrichment score.

Fig. 4. Differentially expressed genes in cavernous nerve injury (CNI)- and diabetes-induced erectile dysfunction (ED) models identified by analysis of microarrays (SAM) analysis. Volcano plots depicted the magnitude of fold change and significance of p-value of the genes identified by SAM in CNI- (A) or diabetes-induced ED (B) models. The x-axis represents log2 fold change and the y-axis log10 p-value. (C) Forty-six genes were commonly up-regulated, and (D) 77 genes were commonly down-regulated in CNI- and diabetes-induced ED models. The diabetic-induced ED data is taken from GSE2457 [10].