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

被引:59
作者
Musicki, B [1 ]
Kramer, MF [1 ]
Becker, RE [1 ]
Burnett, AL [1 ]
机构
[1] Johns Hopkins Univ Hosp, Brady Urol Inst, Baltimore, MD 21287 USA
关键词
penis; eNOS; age;
D O I
10.1111/j.1743-6109.2005.20349.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:347 / 355
页数:9
相关论文
共 39 条
[21]  
GARBAN H, 1995, AM J PHYSIOL, V268, P467
[22]   The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia [J].
Gholami, SS ;
Rogers, R ;
Chang, J ;
Ho, HC ;
Grazziottin, T ;
Lin, CS ;
Lue, TF .
JOURNAL OF UROLOGY, 2003, 169 (04) :1577-1581
[23]   Erectile dysfunction in aging: Upregulation of endothelial nitric oxide synthase [J].
Haas, CA ;
Seftel, AD ;
Razmjouei, K ;
Ganz, MB ;
Hampel, N ;
Ferguson, K .
UROLOGY, 1998, 51 (03) :516-522
[24]   Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation [J].
Harris, MB ;
Ju, H ;
Venema, VJ ;
Liang, HY ;
Zou, R ;
Michell, BJ ;
Chen, ZP ;
Kemp, BE ;
Venema, RC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) :16587-16591
[25]   Intracavernosal injections of vascular endothelial growth factor protects endothelial dependent corpora cavernosal smooth muscle relaxation in the hypercholesterolemic rabbit: a preliminary study [J].
Henry, GD ;
Byrne, R ;
Hunyh, TTT ;
Abraham, V ;
Annex, BH ;
Hagen, PO ;
Donatucci, CF .
INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH, 2000, 12 (06) :334-339
[26]   Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection [J].
Hurt, KJ ;
Musicki, B ;
Palese, MA ;
Crone, JK ;
Becker, RE ;
Moriarity, JL ;
Snyder, SH ;
Burnett, AL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (06) :4061-4066
[27]   Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor - Implications for the vascular responses to cyclosporin A [J].
Kou, RQ ;
Greif, D ;
Michel, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (33) :29669-29673
[28]   The effect of vascular endothelial growth factor on a rat model of traumatic arteriogenic erectile dysfunction [J].
Lee, MC ;
El-Sakka, AI ;
Graziottin, TM ;
Ho, HC ;
Lin, CS ;
Lue, TF .
JOURNAL OF UROLOGY, 2002, 167 (02) :761-767
[29]   Cyclic AMP and cyclic GMP activate protein kinase G in cavernosal smooth muscle cells: old age is a negative factor [J].
Lin, CS ;
Liu, X ;
Chow, S ;
Lue, TF .
BJU INTERNATIONAL, 2002, 89 (06) :576-582
[30]   Enhanced electron flux and reduced calmodulin dissociation may explain "calcium-independent" eNOS activation by phosphorylation [J].
McCabe, TJ ;
Fulton, D ;
Roman, LJ ;
Sessa, WC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (09) :6123-6128