Low androgen level impairs erectile function of rat by regulating the Ng/CaN/AKT/eNOS pathway in penile corpus cavernosum

Zhao, Yue; Wu, Zexiu; Zhao, Xin; Jiang, Jun; Jiang, Rui

doi:10.1111/andr.13202

Cited by 8 publications

(9 citation statements)

References 24 publications

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“…The erectile function of castrated rats was improved after testosterone supplementation. This is consistent with the results from previous studies 30,31 …”

Section: Discussionsupporting

confidence: 94%

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Methylation of eNOS in the rat penile corpus cavernosum under different pathological states and its relationship with erectile function

et al. 2023

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BackgroundIt has been shown that methylation in the promoter region of eNOS can downregulate eNOS expression resulting in the endothelial dysfunction. However, it is unclear whether low androgen levels and type 1 diabetes cause ED by methylating the promoter region of eNOS in the penile corpus cavernosum.ObjectiveTo clarify the effects of type 1 diabetes and hypo‐androgen status on the methylation level of the promoter region of the eNOS gene in penile cavernous tissue and their relationship with the erectile function.MethodsFifty‐eight eight‐week‐old male Sprague–Dawley rats were randomly divided into six groups (n = 6): sham operation group, castration group, castration+testosterone (cast+T) group, normoglycemia group, diabetic group, and diabetic+methyltransferase inhibitor (5‐aza‐dc, 1.5 mg/kg) group. The ICPmax/MAP, serum T, the concentration of nitric oxide (NO), the expression of DNMT1, DNMT3a, DNMT3b, and eNOS, and the methylation level of the eNOS promoter region in penile corpus cavernosum of rat were examined 4 weeks after surgery in the sham‐operated group, the castration group, and the castration + testosterone replacement group. Those tests were examined after 6 weeks using of methylation inhibitors in the normoglycemic group, the diabetic group, and the diabetic + methylation inhibitor group.ResultsICPmax/MAP, DNMT1, DNMT3a, DNMT3b, eNOS, and NO levels were significantly lower in castrated rats than in sham and cast+T rats (P < 0.05). ICPmax/MAP, eNOS, and NO levels were lower, and DNMT1, DNMT3a, and DNMT3b expression levels were significantly increased in the diabetic group compared with the normoglycemic and diabetic+methyltransferase inhibitor groups (P < 0.05). There was no significant difference in the methylation level of the promoter region of eNOS in penile cavernous tissue of castrated rats compared with the sham group or the testosterone replacement group. The methylation level of the promoter region of eNOS in penile cavernous tissue was significantly higher in the diabetic group than in the normoglycemic group and diabetic+methyltransferase inhibitor group (P < 0.05).ConclusionAlthough low androgen status inhibited the level of methyltransferase in rat penile cavernous tissue, did not affect the level of methylation in the promoter region of eNOS. Hyperglycemia inhibits the NO level in the penile cavernous tissue and the erectile function of rats by upregulating the methyltransferase level in the penile cavernous tissue and the methylation level in the promoter region of eNOS. Methylation inhibitors can partly improve the erectile function in type 1 diabetic rats.

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“…The erectile function of castrated rats was improved after testosterone supplementation. This is consistent with the results from previous studies 30,31 …”

Section: Discussionsupporting

confidence: 94%

“…This is consistent with the results from previous studies. 30,31 This is the first report showing that DNMT1, DNMT3a, and DNMT3b are expressed in the nucleus and cytoplasm of smooth muscle cells and endothelial cells in rat penile corpus cavernosum.…”

Section: Discussionmentioning

confidence: 89%

Methylation of eNOS in the rat penile corpus cavernosum under different pathological states and its relationship with erectile function

et al. 2023

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“…At the same time, the same amount of empty lentivirus was injected into the penis of the castrated + empty vector group rats in the same way, while the rats in the other groups were injected with the same doses of physiological saline. After 3 min of injection, the rubber band tied to the penile root of the rat was removed ( 3 , 4 ). The experimental rats were all raised in the Animal Experiment Center of Southwest Medical University.…”

Section: Methodsmentioning

confidence: 99%

“…An incision was made in the abdomen to expose the prostate gland of the rats. After the cavernous nerve was found out, electrical stimulation was performed on it (intensity was 3 V, 5 V, wave amplitude of 5 ms, frequency of 12 Hz, duration of 30 s, interval of 3 min).The ICPmax/MAP was used to erectile function assessment ( 4 ).…”

Section: Methodsmentioning

confidence: 99%

“…Androgen is responsible for maintaining the normal function and structure of the penile corpus cavernosum. The low androgen status can reduce the production of nitric oxide (NO) and inhibit erectile function through the protein kinase B/eNOS (AKT/eNOS) pathway ( 4 ). Hypertension, diabetes, and low androgen status can significantly increase the bioactivity and expression of the ras homolog gene family, member A/Rho-associated coiled-coil forming protein kinase (RhoA/ROCK) in the penile cavernous tissue of rats ( 5 - 8 ), which enhances the contraction of smooth muscle cells and inhibits the erectile function of rats.…”

Section: Introductionmentioning

confidence: 99%

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A low androgen state impairs erectile function by suppressing EPAC1 in rat penile corpus cavernosum

Lin,

Long,

Liu

et al. 2023

Transl Androl Urol

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Background Exchange proteins activated by cAMP 1 ( EPAC1 ) can promote vasodilatation by regulating endothelial nitric oxide synthase (eNOS) activity through the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway and prevent vascular smooth muscle contraction by restraining the ras homolog gene family, member A/Rho-associated coiled-coil forming protein kinase (RhoA/ROCK) pathway. However, the relationship among EPAC1 , androgen and erectile function is still unknown. Therefore, we attempted to investigate whether EPAC1 expresses in penile corpus cavernosum of rats and how EPAC1 affects erectile function under low androgenic conditions. Methods Thirty 8-week-old Sprague-Dawley male rats were randomly divided into six groups (n=5): sham operation (sham), castrated, castrated + testosterone replacement (castrated + T), sham + EPAC1 over-expression lentivirus (sham + EPAC1 ), castrated + empty lentivirus vector (castrated + empty vector), and castrated + EPAC1 . Four weeks after the operation, the lentivirus vectors carrying the EPAC1 gene were injected into the penile corpus cavernosum of the sham + EPAC1 and castrated + EPAC1 groups (1×10 8 TU/mL, 20 µL per rat). A week after injection, the ratio of maximum intracavernous pressure to mean arterial pressure (ICPmax/MAP) and the levels of serum testosterone (T), nitric oxide (NO), the active form of RhoA (RhoA-GTP), AKT, phospho-AKT (p-AKT), eNOS, phospho-eNOS (p-eNOS), p-AKT/AKT, p-eNOS/eNOS and EPAC1 levels were measured. Results In comparison to the sham group, ICPmax/MAP and EPAC1 content in the castrated group were significantly reduced. EPAC1 is primarily located in the cyto-membrane and cytoplasm of endothelial cells and smooth muscle cells in the rat penile corpus cavernosum. In comparison to the sham group, the T, ICPmax/MAP and NO levels of the castrated group were significantly reduced (P<0.01). Meanwhile, the RhoA-GTP concentration in the castrated + EPAC1 group was reduced in comparison with the castrated + empty vector group (P<0.01). Compared with the castrated + empty vector group, the p-AKT/AKT, EPAC1 and p-eNOS/eNOS levels in the castrated + EPAC1 group were significantly increased (P<0.05). Conclusions Androgen deficiency can suppress EPAC1 expression in the penile corpus cavernosum of rats, while the up-regulation of which can improve the erectile function of castrated rats.

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Endothelial Neurogranin Regulates Blood–Brain Barrier Permeability via Modulation of the AKT Pathway

Akande,

Carter,

Stokes

et al. 2024

Mol Neurobiol

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Neurogranin (Ng) expression is a biomarker for Alzheimer’s disease. A loss of brain Ng and an increase in CSF Ng positively correlate with cognitive decline. Ng is known to regulate neuronal calcium-calmodulin binding and synaptic plasticity, which are critical for learning/memory. Interestingly, we discovered that Ng is also expressed in mouse and human blood–brain barrier (BBB). However, the role of Ng expression in brain vasculature remains largely undefined. In this study, we investigated the role of Ng expression on neurovascular structure and function using Ng null mice and human cerebral microvascular endothelial (hCMEC/D3) cells. We performed brain clearing and immunolabeling of blood vessels from whole brains and brain slices. Deletion of Ng significantly decreases neurovascular density in mice. Using in vivo permeability assays, we found increased neurovascular permeability in Ng null mice. We also observed significant changes in the expression of tight junction proteins using western blot and immunofluorescent staining. To identify the molecular pathways involved, we carried out label-free proteomics on brain lysates from endothelial-specific Ng knockout mice. Ingenuity Pathway Analysis indicated that the AKT pathway is attenuated in the vasculature of endothelial-specific Ng knockout mice. To validate these in vivo findings, we pharmacologically manipulated AKT signaling in hCMEC/D3 cells and observed that inhibition of AKT activation causes increased permeability. Our results indicate that the loss of Ng expression alters neurovascular structure and permeability, potentially contributing to neurological dysfunction. Therefore, modulating Ng expression in the BBB may offer a novel therapeutic approach for Alzheimer’s disease.

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Low androgen level impairs erectile function of rat by regulating the Ng/CaN/AKT/eNOS pathway in penile corpus cavernosum

Cited by 8 publications

References 24 publications

Methylation of eNOS in the rat penile corpus cavernosum under different pathological states and its relationship with erectile function

Methylation of eNOS in the rat penile corpus cavernosum under different pathological states and its relationship with erectile function

A low androgen state impairs erectile function by suppressing EPAC1 in rat penile corpus cavernosum

Endothelial Neurogranin Regulates Blood–Brain Barrier Permeability via Modulation of the AKT Pathway

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