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研究生:曾文民
研究生(外文):Wen-Min Tseng
論文名稱:低氧對小鼠TM3萊氏細胞分泌睪酮與血管內皮生長因子之效應
論文名稱(外文):Effects of Hypoxia on the Release of Testosterone and Vascular Endothelial Growth Factor in Mouse TM3 Leydig Cells
指導教授:王錫崗王錫崗引用關係
指導教授(外文):Paulus S. Wang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:65
中文關鍵詞:低氧萊氏細胞睪酮血管內皮生長因子
外文關鍵詞:HypoxiaLeydig CellTestosteroneVascular Endothelial Growth Factor
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本實驗室以前的研究指出,間歇性低氧會升高大鼠血漿睪酮濃度,此外亦可增加人類絨毛促性腺激素對萊氏細胞的刺激效應,並發現睪丸有血管新生的現象。在多數的細胞,低氧會刺激表現血管內皮生長因子,其為血管新生與生成之重要介質。因此在低氧的環境下,血管內皮生長因子可能造成睪丸的血管新生。然而,血管內皮生長因子對萊氏細胞固醇類激素生合成睪酮的影響尚不清楚。本論文選用小鼠TM3萊氏細胞株作為研究的模式。在低氧的條件中,培養TM3萊氏細胞於低氧艙中,並充以95 %的氮氣與5 %的二氧化碳,低氧培養約1至24小時。收集培養後的細胞培養液,以放射免疫測定法檢測睪酮濃度,以酵素免疫測定法檢測血管內皮生長因子濃度。收集培養後的細胞,分離細胞質蛋白與細胞核蛋白,以西方墨漬分析法檢測細胞內蛋白質的表現。以MTT測試法偵測萊氏細胞的增殖效應。結果顯示在低氧的情況下萊氏細胞明顯的增殖。在低氧經人類絨毛促性腺激素或血管內皮生長因子處理,會明顯的刺激萊氏細胞增生,而在處理血管內皮生長因子的抗體時,則可阻滯其增生效應。在低氧的環境下,血管內皮生長因子的基礎釋放會提高,且對於人類絨毛促性腺激素的刺激血管內皮生長因子的分泌效應亦增高。進一步的研究指出,低氧會刺激HIF-1α的表現,導致血管內皮生長因子的釋放。但低氧卻未影響萊氏細胞的睪酮分泌。探討訊息傳導路徑,顯示P-ERK1/2可經由低氧與人類絨毛促性腺激素刺激而表現增加。而藉由MEK的抑制劑-PD98059可抑制經由低氧與人類絨毛促性腺激素刺激血管內皮生長因子釋放的效應。PD98059亦可抑制人類絨毛促性腺激素所引起睪酮的釋放。血管內皮生長因子與睪酮之間亦產生交互效應。睪酮對萊氏細胞分泌血管內皮生長因子並無影響。相反的,高濃度的血管內皮生長因子可刺激睪酮的釋放,呈劑量反應的效應。處理血管內皮生長因子的抗體時,則可阻滯其血管內皮生長因子對睪酮的刺激效應。另有結果顯示,血管內皮生長因子會提高細胞內P-ERK1/2表現的增加,PD98059可抑制血管內皮生長因子所引起的P-ERK1/2的高度表現。綜合以上結果,推論低氧造成睪酮的分泌的上升,部分原因是由於藉由高度釋放的血管內皮生長因子,對於萊氏細胞的增生效應,或是藉此刺激萊氏細胞分泌睪酮。低氧造成血管內皮生長因子與睪酮的釋放可能透過ERK1/2的訊息傳導路徑。這些結果與推測,顯示在低氧的情況下,血管內皮生長因子對於萊氏細胞的固醇類激素生合成效應,可能具有一重要之地位。未來將可進一步清楚的探討睪酮與其他低氧因子之間的調控機制。
Previous studies indicated that intermittent hypoxia resulted in an enhancement of plasma testosterone, increased response of Leydig cells to human chorionic gonadotropin (hCG), and angiogenesis in rat testes. Hypoxia has been shown to stimulate the expression of vascular endothelial growth factor (VEGF), which is a major mediator for angiogenesis and vasculogenesis. During hypoxia, VEGF promotes the angiogenesis in the testis. However, the effect of VEGF on the steroidogenesis of testosterone in Leydig cells is not clear. A mouse TM3 Leydig cell line has been used as a research model. Under hypoxic condition, the Leydig cells were incubated in an incubator chamber (95 % N2, 5 % CO2) for 1~24 hours. The cultured media were collected and assayed for testosterone by radioimmunoassay (RIA) and for VEGF by enzyme immunoassay (EIA). The cytosolic and nuclear proteins were extracted and intracellular protein expression was determined by Western blot. MTT test was used for detecting the proliferation of Leydig cells. The present data showed that the proliferation of Leydig cells was enhanced significantly under hypoxia condition. During hypoxia, administration of hCG or VEGF could stimulate proliferation of Leydig cells, but the stimulatory effect was abolished by the administration of anti-VEGF antibody. The basal release of VEGF was increased, and the response of VEGF production to hCG was also enhanced in hypoxic condition. Furthermore, induced expression of hypoxia inducible factor-1α (HIF-1α) in Leydig cells resulted in an increase of VEGF release. Hypoxia failed to cause an increase of testosterone release in Leydig cells. Expression of phospho-extracellular signal-regulated kinase 1 and 2 (P-ERK1/2) was enhanced in response to hypoxia or hCG treatment. PD98059 (an inhibitor of MEK) inhibited the hCG or hypoxia-induced VEGF release and diminished the hCG-stimulated testosterone release. Meanwhile, the interaction between VEGF and testosterone were also investigated. Testosterone did not affect VEGF release in Leydig cells, but higher dose of VEGF could stimulate testosterone release in a dose dependent manner. Administration of anti-VEGF antibody abolished the stimulatory effect of VEGF on testosterone release. Expression of P-ERK1/2 was enhanced after treatment with VEGF. PD98059 inhibited VEGF-induced P-ERK1/2 expression. These data demonstrated that the enhancement of testosterone release during hypoxia was resulted from proliferation of Leydig cells by an increase of VEGF generation. Apparently, VEGF plays an important role in regulating steroidogenesis of testosterone in Leydig cells during hypoxia.
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