Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes
Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes
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DOI：
10.1677/jme.0.0310401
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Kitabatake, A
中科院分区：
文献类型：
--
作者：
Jesmin, S;Sakuma, I;Kitabatake, A
勃起功能障碍（艾德）是男性糖尿病患者的常见疾病。血管内皮生长因子（VEGF）在糖尿病不同并发症中的致病作用已被广泛报道。我们假设VEGF、其受体和其信号通路Akt的表达在糖尿病阴茎组织中可能发生显著改变，并且它们的改变可能调节被认为在糖尿病ED中起作用的分子的阴茎表达。在II型糖尿病的胰岛素抵抗阶段（20周龄）使用（非胰岛素依赖性）糖尿病的小鼠。我们采用免疫组化、Western印迹、原位杂交和实时定量PCR分析，确定了阴茎中VEGF、其受体、Akt、一氧化氮合酶亚型和前列腺增生相关分子的蛋白质和mRNA表达。阴茎切片也提交给Tdt介导的dUTP缺口末端标记法用于细胞凋亡。OLETF大鼠阴茎VEGF、其两种受体和Akt的表达显著降低。在OLETF大鼠阴茎中，内皮和神经元型一氧化氮合酶亚型表达较少。此外，虽然抗凋亡标记物Bcl-2和磷酸化Bad下调，但促凋亡标记物活性caspase-3和Bax上调，导致OLETF大鼠阴茎组织中出现凋亡细胞。由于表达减少，VEGF信号系统在糖尿病阴茎组织中的作用较差，导致内皮细胞产生的一氧化氮减少和勃起相关的勃起组织损伤。我们认为阴茎中VEGF信号系统的异常可能在糖尿病性ED的病理生理学中发挥作用。
Erectile dysfunction (ED) is commonly experienced in men with diabetes mellitus. Vascular endothelial growth factor (VEGF) has been extensively documented for its pathogenic significance in different complications of diabetes. We hypothesized that expressions of VEGF, its receptors and its signaling pathway Akt may be drastically altered in diabetic penile tissues and their alterations may modulate penile expression of the molecules that are believed to play a role in diabetic ED. Otsuka Long-Evans Fatty (OLETF) rats, a type II (non-insulin-dependent) diabetes mellitus, were used at the insulin-resistant stage of type II diabetes (20 weeks of age). We determined protein and mRNA expressions of VEGF, its receptors, Akt, nitric oxide synthase isoforms, and apoptosis-related molecules in the penis using immunohistochemistry, Western blotting, in situ hybridization, and real-time quantitative PCR analyses. The penile sections were also submitted to the Tdt-mediated dUTP nick end labeling assay for apoptosis. OLETF rats showed marked reductions in penile expression of VEGF, its two receptors and Akt. In OLETF rat penises, endothelial and neuronal nitric oxide synthase isoforms were expressed less abundantly. Furthermore, while anti-apoptotic markers, Bcl-2 and phosphorylated Bad, were down-regulated, pro-apoptotic markers, active caspase-3 and Bax, were up-regulated, resulting in the appearance of apoptotic cells in the penile tissues of OLETF rats. The VEGF signaling system would work less well in diabetic penile tissues as a result of the reduced expression, leading to diminished endothelial production of nitric oxide and apoptosis-related erectile tissue damage. We propose that the abnormalities of the VEGF signaling system in the penis may play a role in the pathophysiology of diabetic ED.