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Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorates erectile dysfunction through Lipocalin 2 in the diabetic mice

ABSTRACT: Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Due to neurovascular dysfunction, men with diabetic ED do not respond well to oral phosphodiesterase 5 inhibitors. Pericyte-derived extracellular vesicles-mimetic nanovesicles (PC-NVs) are known to play a role in promoting nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs can effectively promote penile angiogenesis and neural regeneration, thereby improving erectile function under diabetic conditions. We found that PC-NVs can induce endothelial proliferation, migration, and reduce cell apoptosis under diabetic conditions. In addition, PC-NVs induce neural regeneration in STZ-induced diabetic mice in vivo and ex vivo MPG or DRG explants under high-glucose conditions. We found that Lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, indicating that PC-NVs exert their angiogenesis and nerve regeneration effects by activating MAP kinase, PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner under diabetic conditions. Our findings provide new conclusive evidence that PC-NVs mediate neurovascular regeneration and erectile function recovery under diabetic conditions through an Lcn2-dependent mechanism. Local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED.

ORGANISM(S): Mus musculus

PROVIDER: GSE183220 | GEO | 2022/07/13

REPOSITORIES: GEO

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Project description:Background: There is growing evidence that circular RNAs (circRNAs) play an important role in a variety of diseases, including erectile dysfunction (ED). Nevertheless, the role of circRNAs in cavernous nerve-damaging ED (CNI-ED) is unknown. Here, we aimed to discover new circRNAs, investigate their potential role in the pathogenesis of CNI-ED, and construct a circRNA-miRNA-mRNA network. Methods: Twelve male Sprague Dawley rats were randomly divided into bilateral cavernous nerve crush (BCNC) and control groups. Four weeks after surgery, the spongy smooth muscle tissue of the rat penis was sequenced using high-throughput full transcriptome sequencing. We analyzed the expression profiles of circRNAs, miRNAs, and mRNAs in the two groups. Twenty circRNAs with significantly different expressions were selected for real-time polymerase chain reaction (RT-qPCR). The circRNA-miRNA-mRNA network was established using Cytoscape. Gene ontology (GO)-term and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the edgeR package. Results: RNA transcriptome sequencing showed that 4,587 circRNAs, 762 miRNAs, and 21,661 mRNAs were dysregulated in the BCNC group. The top 20 differentially expressed circRNAs were further verified via RT-qPCR. The ceRNA network contained 23 circRNA-miRNA pairs and 227 miRNA-mRNA pairs, including ten circRNAs, six miRNAs, and 227 mRNAs. GO analysis suggested that these ten circRNAs could regulate various processes, such as oxidation-reduction processes, lipid metabolic processes, apoptotic processes, and proteolysis. Furthermore, KEGG analysis of mRNAs in the ceRNA network showed that they were involved in energy metabolism and communication between cells. A protein‐protein interaction network was constructed with the 227 mRNAs, and five hub genes (Ccna2, Cxcl10, Pld1, Mapk11, and Mboat2) were identified. In addition, Using circRNADb, we found 12 circRNAs with protein-coding potential, three of which were highly conserved in humans and rats. Our study revealed a potential link between circRNAs, miRNAs, and mRNAs in CNI-ED, suggesting that circRNAs may contribute to the occurrence of ED by regulating the cellular energy metabolism in CNI-ED.

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Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorates erectile dysfunction through Lipocalin 2 in the diabetic mice

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