Aim. Aging is associated with erectile dysfunction (ED) attributed to reduced nitric oxide synthase (NOS) activity and nitric oxide bioavailability, However, the mechanism for this effect has not been fully investigated. We evaluated (i) whether age-related ED involves dysregulation of endothelial NOS (eNOS) phosphorylation; and (ii) whether vascular endothelial growth factor (VEGF) exerts erectile effects and operates via eNOS phosphorylation in aged rats. Methods. Male Fischer 344 "young" (4-month-old) and "aged" (19-month-old) rats were used. Electrical stimulation of the cavernous nerve (CNS) was performed to generate penile erection. Erectile response in the presence of rhVEGF165 was evaluated by intracavernosal pressure monitoring 25 minutes after intracavernosal injection of VEGF. Penes were excised at baseline, with or without rhVEGF treatment, and after CNS for Western immunoblot of phospho-eNOS (Ser-1177 and Thr-495), phospho-Akt, and eNOS. Results. Erectile response was significantly reduced in aged rats compared with young rats. Phospho-eNOS (Ser-1177) and phospho-Akt were significantly reduced, while phospho-eNOS (Thr-495) was significantly increased, in the aged penis at baseline and after CNS. rhVEGF significantly improved erection and reversed downregulated Ser-1177, but not upregulated Thr-495 phosphorylation, on eNOS in aged penes. eNOS protein was significantly increased in aged penes. Conclusions. Age-related ED is associated with eNOS inactivation through a decrease in phosphorylation of its positive regulatory site (Ser-1177) and an increase in phosphorylation of its negative regulatory site (Thr-495) in the penis. Altered phosphorylation/constitutive activation of eNOS by fluid shear stress may be a major determinant of compromised vascular homeostasis of the aged penis. The finding that VEGF rapidly induces erection and partly corrects alterations in eNOS phosphorylation in the aged rat penis suggests impaired eNOS activation by deficient endogenous VEGF and supports the potential for growth factor therapy in the treatment of age-related ED.
机构:
Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USADuke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Henry, GD
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Byrne, R
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Byrne, R
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Hunyh, TTT
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Hunyh, TTT
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Abraham, V
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Abraham, V
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Annex, BH
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Annex, BH
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Hagen, PO
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Hagen, PO
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Donatucci, CF
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lee, MC
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El-Sakka, AI
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
El-Sakka, AI
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Graziottin, TM
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Graziottin, TM
;
Ho, HC
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Ho, HC
;
Lin, CS
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lin, CS
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Lue, TF
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lin, CS
;
Liu, X
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Liu, X
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Chow, S
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Chow, S
;
Lue, TF
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h-index: 0
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
机构:
Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USADuke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Henry, GD
;
Byrne, R
论文数: 0引用数: 0
h-index: 0
机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Byrne, R
;
Hunyh, TTT
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Hunyh, TTT
;
Abraham, V
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Abraham, V
;
Annex, BH
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Annex, BH
;
Hagen, PO
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
Hagen, PO
;
Donatucci, CF
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机构:Duke Univ, Med Ctr, Dept Surg, Div Gen & Thorac Surg,Atherosclerosis Res Lab, Durham, NC 27710 USA
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lee, MC
;
El-Sakka, AI
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h-index: 0
机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
El-Sakka, AI
;
Graziottin, TM
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机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Graziottin, TM
;
Ho, HC
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h-index: 0
机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Ho, HC
;
Lin, CS
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lin, CS
;
Lue, TF
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
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Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Lin, CS
;
Liu, X
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机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Liu, X
;
Chow, S
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机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA
Chow, S
;
Lue, TF
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USAUniv Calif San Francisco, Sch Med, Dept Urol, Knuppe Mol Urol Lab, San Francisco, CA 94143 USA