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Senescent Cells Impair Erectile Function through Induction of Endothelial Dysfunction and Nerve Injury in Mice.

Nishimatsu H, Suzuki E, Saito Y, Niimi A, Nomiya A, Fukuhara H, Kume H, Homma Y - PLoS ONE (2015)

Bottom Line: Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection.These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury.These effects may be mediated by proinflammatory cytokines produced by senescent cells.

View Article: PubMed Central - PubMed

Affiliation: The Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Erectile dysfunction (ED) is a major health problem, particularly in the elderly population, which is rapidly increasing. It is necessary to elucidate the mechanism by which ED occurs in the elderly. Cellular senescence is commonly detected in old tissues, and it is well known that senescent cells not only withdraw from the cell cycle but also remain viable and actively produce a variety of cytokines. We examined the effect of senescent cells on erectile function after injection of senescent cells into the penises of mice. Human umbilical vein endothelial cells were infected with an adenovirus expressing a constitutively active mutant of Ras to induce senescence, and were injected into the penises of nude mice. These senescent cells expressed proinflammatory cytokines such as interleukin-1β (IL-1β). Injection of senescent cells impaired erectile function, as assessed by the measurement of intracavernous pressure. Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection. The penises injected with the senescent cells expressed human IL-1β and subsequently endogenous proinflammatory cytokines such as mouse IL-1β and tumor necrosis factor-α. These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury. These effects may be mediated by proinflammatory cytokines produced by senescent cells.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of VE-Cad, SMA, phospho-eNOS, total eNOS, and nNOS expressions.A) The penises were isolated for protein extraction 2 weeks after the AdGFP_HUVECs injection, and 2 (2W), 4 (4W), and 6 (6W) weeks after the AdRas12V_HUVECs injection. Proteins were also extracted from age-matched control mice (Control). Representative photographs are shown. B) Histograms showing the relative intensity of the bands (n = 4 per group). * and **: P<0.05 and P<0.01, respectively vs. AdGFP_HUVECs injection. T-eNOS: total eNOS.
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pone.0124129.g005: Western blot analysis of VE-Cad, SMA, phospho-eNOS, total eNOS, and nNOS expressions.A) The penises were isolated for protein extraction 2 weeks after the AdGFP_HUVECs injection, and 2 (2W), 4 (4W), and 6 (6W) weeks after the AdRas12V_HUVECs injection. Proteins were also extracted from age-matched control mice (Control). Representative photographs are shown. B) Histograms showing the relative intensity of the bands (n = 4 per group). * and **: P<0.05 and P<0.01, respectively vs. AdGFP_HUVECs injection. T-eNOS: total eNOS.

Mentions: To quantify the markers for blood vessels and nitrergic nerves, Western blot analysis was performed (Fig 5). VE-Cad expression significantly decreased at 2 and 4 weeks after AdRas12V_HUVECs injection compared with AdGFP_HUVECs injection. Its expression recovered 6 weeks after AdRas12V_HUVECs injection. In contrast, SMA and total eNOS expressions did not significantly change after AdRas12V_HUVECs injection. These results were in marked contrast to those observed in the penises of diabetic rats, where SMA expression significantly decreased compared with that in non-diabetic control rats [21, 28]. Interestingly, the expression of phospho-eNOS, which is phosphorylated at Ser1177 and catalytically active, remained significantly low at 2, 4, and 6 weeks after the AdRas12V_HUVECs injection compared with that after the AdGFP_HUVECs injection. The ratio of phospho-eNOS to total eNOS also remained significantly low in the AdRas12V_HUVECs-injected group compared with that in the AdGFP_HUVECs-injected group. These results suggested that although the vascular structure in the penis was relatively conserved after injection of AdRas12V_HUVECs, endothelial dysfunction occurred. nNOS expression significantly decreased at 2 and 4 weeks after the AdRas12V_HUVECs injection, and the expression remained low 6 weeks later compared with that after the AdGFP_HUVECs injection, although the expression was recovering.


Senescent Cells Impair Erectile Function through Induction of Endothelial Dysfunction and Nerve Injury in Mice.

Nishimatsu H, Suzuki E, Saito Y, Niimi A, Nomiya A, Fukuhara H, Kume H, Homma Y - PLoS ONE (2015)

Western blot analysis of VE-Cad, SMA, phospho-eNOS, total eNOS, and nNOS expressions.A) The penises were isolated for protein extraction 2 weeks after the AdGFP_HUVECs injection, and 2 (2W), 4 (4W), and 6 (6W) weeks after the AdRas12V_HUVECs injection. Proteins were also extracted from age-matched control mice (Control). Representative photographs are shown. B) Histograms showing the relative intensity of the bands (n = 4 per group). * and **: P<0.05 and P<0.01, respectively vs. AdGFP_HUVECs injection. T-eNOS: total eNOS.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4404101&req=5

pone.0124129.g005: Western blot analysis of VE-Cad, SMA, phospho-eNOS, total eNOS, and nNOS expressions.A) The penises were isolated for protein extraction 2 weeks after the AdGFP_HUVECs injection, and 2 (2W), 4 (4W), and 6 (6W) weeks after the AdRas12V_HUVECs injection. Proteins were also extracted from age-matched control mice (Control). Representative photographs are shown. B) Histograms showing the relative intensity of the bands (n = 4 per group). * and **: P<0.05 and P<0.01, respectively vs. AdGFP_HUVECs injection. T-eNOS: total eNOS.
Mentions: To quantify the markers for blood vessels and nitrergic nerves, Western blot analysis was performed (Fig 5). VE-Cad expression significantly decreased at 2 and 4 weeks after AdRas12V_HUVECs injection compared with AdGFP_HUVECs injection. Its expression recovered 6 weeks after AdRas12V_HUVECs injection. In contrast, SMA and total eNOS expressions did not significantly change after AdRas12V_HUVECs injection. These results were in marked contrast to those observed in the penises of diabetic rats, where SMA expression significantly decreased compared with that in non-diabetic control rats [21, 28]. Interestingly, the expression of phospho-eNOS, which is phosphorylated at Ser1177 and catalytically active, remained significantly low at 2, 4, and 6 weeks after the AdRas12V_HUVECs injection compared with that after the AdGFP_HUVECs injection. The ratio of phospho-eNOS to total eNOS also remained significantly low in the AdRas12V_HUVECs-injected group compared with that in the AdGFP_HUVECs-injected group. These results suggested that although the vascular structure in the penis was relatively conserved after injection of AdRas12V_HUVECs, endothelial dysfunction occurred. nNOS expression significantly decreased at 2 and 4 weeks after the AdRas12V_HUVECs injection, and the expression remained low 6 weeks later compared with that after the AdGFP_HUVECs injection, although the expression was recovering.

Bottom Line: Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection.These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury.These effects may be mediated by proinflammatory cytokines produced by senescent cells.

View Article: PubMed Central - PubMed

Affiliation: The Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Erectile dysfunction (ED) is a major health problem, particularly in the elderly population, which is rapidly increasing. It is necessary to elucidate the mechanism by which ED occurs in the elderly. Cellular senescence is commonly detected in old tissues, and it is well known that senescent cells not only withdraw from the cell cycle but also remain viable and actively produce a variety of cytokines. We examined the effect of senescent cells on erectile function after injection of senescent cells into the penises of mice. Human umbilical vein endothelial cells were infected with an adenovirus expressing a constitutively active mutant of Ras to induce senescence, and were injected into the penises of nude mice. These senescent cells expressed proinflammatory cytokines such as interleukin-1β (IL-1β). Injection of senescent cells impaired erectile function, as assessed by the measurement of intracavernous pressure. Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection. The penises injected with the senescent cells expressed human IL-1β and subsequently endogenous proinflammatory cytokines such as mouse IL-1β and tumor necrosis factor-α. These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury. These effects may be mediated by proinflammatory cytokines produced by senescent cells.

No MeSH data available.


Related in: MedlinePlus