Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis

Biljana Musicki, Melissa F. Kramer, Robyn E. Becker, Arthur Burnett, Iñigo Sáenz De Tejada

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalJournal of Sexual Medicine
Volume2
Issue number3
DOIs
StatePublished - 2005

Fingerprint

Penis
Phosphorylation
Erectile Dysfunction
Vascular Endothelial Growth Factor A
Penile Erection
Nitric Oxide Synthase Type III
rat Nos3 protein
Nitric Oxide Synthase
Electric Stimulation
Biological Availability
Blood Vessels
Intercellular Signaling Peptides and Proteins
Nitric Oxide
Homeostasis
Therapeutics
Down-Regulation
Western Blotting
Pressure
Injections
Proteins

Keywords

  • Age
  • eNOS
  • Penis

ASJC Scopus subject areas

  • Urology
  • Obstetrics and Gynecology

Cite this

Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. / Musicki, Biljana; Kramer, Melissa F.; Becker, Robyn E.; Burnett, Arthur; De Tejada, Iñigo Sáenz.

In: Journal of Sexual Medicine, Vol. 2, No. 3, 2005, p. 347-357.

Research output: Contribution to journalArticle

Musicki, Biljana ; Kramer, Melissa F. ; Becker, Robyn E. ; Burnett, Arthur ; De Tejada, Iñigo Sáenz. / Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. In: Journal of Sexual Medicine. 2005 ; Vol. 2, No. 3. pp. 347-357.
@article{4573b9c341524b81ae9d5acef68117c4,
title = "Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis",
abstract = "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.",
keywords = "Age, eNOS, Penis",
author = "Biljana Musicki and Kramer, {Melissa F.} and Becker, {Robyn E.} and Arthur Burnett and {De Tejada}, {I{\~n}igo S{\'a}enz}",
year = "2005",
doi = "10.1111/j.1743-6109.2005.20349.x",
language = "English (US)",
volume = "2",
pages = "347--357",
journal = "Journal of Sexual Medicine",
issn = "1743-6095",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis

AU - Musicki, Biljana

AU - Kramer, Melissa F.

AU - Becker, Robyn E.

AU - Burnett, Arthur

AU - De Tejada, Iñigo Sáenz

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

KW - Age

KW - eNOS

KW - Penis

UR - http://www.scopus.com/inward/record.url?scp=19744372761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19744372761&partnerID=8YFLogxK

U2 - 10.1111/j.1743-6109.2005.20349.x

DO - 10.1111/j.1743-6109.2005.20349.x

M3 - Article

C2 - 16422866

AN - SCOPUS:19744372761

VL - 2

SP - 347

EP - 357

JO - Journal of Sexual Medicine

JF - Journal of Sexual Medicine

SN - 1743-6095

IS - 3

ER -