β-catenin 訊息路徑在動靜脈廔管病變之角色

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題名:	β-catenin 訊息路徑在動靜脈廔管病變之角色 The Role of β-catenin Signaling Pathway in Pathogenesis of Arteriovenous Fistula Lesion
作者:	劉崇德 Liu, Chung-Te
貢獻者:	臨床醫學研究所博士班施俊明林豐彥黃柏勳
關鍵詞:	動靜脈廔管;β-連環蛋白;末期腎病;血液透析;血液透析;肌成纖維細胞 arteriovenous fistula;β-catenin;end-stage renal disease;hemodialysis;parathyroid hormone;myofibroblast
日期:	2022-01-17
上傳時間:	2022-08-09 10:39:40 (UTC+8)
摘要:	動靜脈廔管為血液透析病患維繫生命之重要血管通路。在各種血液透析血管通路中，動靜脈廔管有較佳之長期暢通率以及較低之血流感染率，故動靜脈廔管為血液透析治療指引中血管通路之首選。然而因廔管成熟率偏低以及長期使用後廔管狹窄等問題，動靜脈廔管也非完美之血管通路。病理分析上，造成動靜脈廔管病變之原因為內皮下層之肌成纖維細胞(myofibroblast)增多，一方面限制了廔管之外向擴張(outward remodeling)，一方面也擠壓管腔造成廔管阻塞狹窄。由此可知，控制肌成纖維細胞之增生為改善動靜脈廔管成熟率以及暢通率之重要因素。 β-catenin位於內皮細胞之細胞膜上，其功能為細胞黏附以維持內皮之構型。另一方面，β-catenin也是啟動內皮細胞轉型為間質細胞(如: 肌成纖維細胞)之訊息路徑。以往研究發現，物理性或化學性刺激皆會干擾內皮細胞膜上之β-catenin而啟動β-catenin訊息路徑，造成內皮細胞之變性轉型，進而導致各種血管病變。本研究之目的為證實β-catenin訊息路徑之活化在動靜脈廔管內造成肌成纖維細胞之增加，隨之造成廔管病變之形成。首先，在接受動靜脈廔管形成術之病患中，我們發現較高的血中副甲狀腺素和較高之廔管不成熟率相關。在小鼠動靜脈廔管模型中，我們發現較高的血中副甲狀腺素會活化β-catenin訊息路徑。另一方面，較高的血中副甲狀腺素也經由增加肌成纖維細胞使廔管病變惡化。在加壓處理之細胞模型中，我們發現物理加壓以及副甲狀腺素協同性地造成血管平滑肌細胞轉型為肌成纖維細胞。以上發現指出物理性刺激以及副甲狀腺素在動靜脈廔管病變之形成皆有其角色。在另一小鼠動靜脈廔管模型中，我們發現β-catenin訊息路徑之活化與內皮細胞間質轉化同時存在。在加壓細胞模型中，我們發現加壓直接引起臍靜脈內皮細胞轉化為肌成纖維細。以上這些變化，皆可經由β-catenin訊息路徑之抑制來反轉。本研究之各項發現指出，不論在血管平滑肌細胞或在內皮細胞，β-catenin訊息路徑之活化在動靜脈廔管病變之形成有重要之影響。在未來，β-catenin訊息路徑之抑制可做為改善廔管成熟或長期暢通率之治療選擇。 Arteriovenous fistula (AVF) is the recommended type of vascular access for hemodialysis patients. While AVF has superior long-term patency and lower infection rates compared with other types of vascular access, it also has flaw including nonmaturation and loss of patency with long-term use. The AVF lesion causing nonmaturation and loss of patency is characterized by accumulation of myofibroblast in subintima. On one hand, the AVF lesion limits the outward remodeling of AVF to impede its maturation; on the other hand, enlarging AVF lesion decreases the diameter of AVF lumen and results in loss of patency. As such, treatment to limit or control the formation of subintimal myofibroblast is critical to improve AVF maturation and to maintain AVF patency. On the cell membrane of endothelial cells, β-catenin is a part of cell-cell adheren complex that functions to maintain the integrity of endothelium. In addition, β-catenin is also a signaling molecule that control the transition from endothelial cell to mesenchymal cell, for example, myofibroblast. It had been reported that mechanical or chemical stimuli disturbed membrane β-catenin to activate β-catenin signaling and induce endothelial-to-mesenchymal transition, which was involved in various types of vasculopathy. The aim of this study is to test the hypothesis that activated β-catenin signaling induces the transition of myofibroblast in AVF and subsequently cause the formation of AVF lesion. In patients receiving AVF creation, we found that elevated plasma PTH level was associated with increased risk of AVF nonmaturation. In mouse AVF model, we showed that higher PTH level activated β-catenin signaling and increased AVF lesion via increasing the transition of myofibroblast. In cell model of pressure-culture system, we showed that pressurization and PTH synergistically increased the transition of vascular smooth muscle cell to myofibroblast. These findings suggested higher PTH level and mechanical stimuli in AVF may both activate β-catenin signaling to increase AVF lesion. In another mouse AVF model, we showed activated β-catenin signaling and endothelial-to-mesenchymal transition on AVF. In the cell model of pressure-culture system, we showed that pressurization activated β-catenin signaling and induce endothelial-to-myofibroblast transition in human umbilical venous endothelial cells. These mechanical-induced cell transition could be reversed by β-catenin inhibition. These findings suggested that the activated β-catenin signaling in endothelial cells play an important role in the formation of AVF lesion, either through its action on vascular smooth muscle cells or endothelial cells. We also demonstrated the potential of β-catenin inhibitors in the prevention of AVF lesion. In future, β-catenin inhibitors may be used to improve AVF maturation or to prevent loss of patency.
描述:	博士指導教授:施俊明共同指導教授:林豐彥共同指導教授:黃柏勳委員:吳麥斯委員:施俊明委員:林豐彥委員:黃柏勳委員:方德昭委員:林志慶委員:呂至剛
資料類型:	thesis
顯示於類別:	[臨床醫學研究所] 博碩士論文

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