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研究生:黃東益
研究生(外文):Tung-Yi Huang
論文名稱:老鼠主動脈內皮細胞鈣離子訊息傳遞及血管反應
論文名稱(外文):The Endothelial [Ca2+]i Signaling and Vascular Responsiveness in Rat Aorta In Situ
指導教授:任卓穎
指導教授(外文):Chauying J. Jen
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:126
中文關鍵詞:內皮細胞鈣離子血管舒張
外文關鍵詞:endothelial cellvasodilatationcalcium
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  人體內不同部位之內皮細胞的表面接受器,訊息傳導路徑與內在基因的表現和生理功能,都有顯著的差異性。例如:從肝臟及腦部的微血管培養出來的內皮細胞,其表面的蛋白質、次級訊息傳遞系統及胞內酵素都有各自的特徵。越來越多的證據顯示特定的心血管疾病會在特定的血管種類出現。此種情況可能源自於血管內皮細胞特有的表現分子所致。因此,對於血管內皮細胞異差性表現的研究,可以提供未來治療血管疾病的研究方向。然而,目前對於血管內皮細胞區域性差異的表現研究仍然不足。
  在主動脈血管分支處,由於其血管的厚度產生劇烈的變化,並且其所受到的血液流洩剪力在此處產生了複雜的血流型態。因此在此處的血管內皮細胞的表現型,可能會因為內在基因或因對環境因子的適應而產生改變。此處之細胞膜表面接受器特徵及訊息傳遞路徑可能受到某種程度的修飾。內皮細胞之胞內鈣離子傳遞路徑為最主要的訊息傳導路徑。若此路徑因環境的挑戰而受到修飾,細胞的表現型將受到極大的改變。故本研究的主要目的就是研究內皮細胞之鈣離子傳遞路徑在老鼠主動脈上之差異表現。
  藉由在血管段內皮細胞鈣離子訊息的研究,作者發現老鼠主動脈內皮細胞之鈣離子訊息傳遞具有刺激劑專一性的差異表現。乙醯膽鹼或組織胺會分別誘導M3及H1接受器亞型的鈣離子上升。乙醯膽鹼在分支處所誘發的鈣離子上升與非分支處相比有較強的反應,然而組織胺在分支處所誘發的反應較不明顯。此外,血管上的內皮細胞,無論是受乙醯膽鹼或組織胺刺激,都有一些細胞鈣離子上升比較強。而這些細胞在血管上升都呈現與血流平行的排列方向。同時,某些對乙醯膽鹼較靈敏的細胞對組織胺反應相對不靈敏。而某些細胞則呈現相反的特徵。在非分支處的細胞對於固定濃度的乙醯膽鹼及組織胺有極大的差異性反應,其相對靈敏度有一百倍的差異。
  內皮細胞主要的生理功能之一是造成血管的放鬆反應。雖然有報告認為體外培養的內皮細胞可以藉由非鈣離子依賴型產生放鬆因子。然而內皮細胞調控血管張力的主要路徑仍是藉由鈣離子濃度調控。在物理及化學因子的刺激下,鈣離子依賴型的酵素活性會伴隨著鈣離子濃度的上升而增加。因為在乙醯膽鹼的作用下鈣離子在分支處有較高的反應,故在某些刺激劑存在的情形下,鈣離子訊息可能會調控血流的分布。然而,胞內鈣離子濃度與血管張力之間是否有定量上的關係仍不清楚。因此,本實驗的另一個目標是研究胞內鈣離子濃度與血管張力之間的定量關係。
  在此,作者研究出一種可在體外血管段上同時測定內皮細胞內鈣離子濃度及血管收縮與放鬆程度的技術。此技術主要是藉由測量鈣離子螢光對此影像及影像之位移程度來同時量化胞內鈣離子濃度與血管張力。由於本系統在流體通過下測量,故較能模擬有血流下之血管生理情況。本實驗結果發現,無論是在流體對血管產生衝擊時,或是流體已經對血管產生一段時間的影響,內皮細胞鈣離子都不會上升,也沒有血管放鬆的情形產生。若血管先給予正腎上腺素的刺激,再以乙醯膽鹼或ionomycin的刺激,則會觀察到胞內鈣離子先上升,然後血管再放鬆。血管的放鬆對於胞內鈣離子的變化非常靈敏。很小的胞內鈣離子上升(<200 nM),就會誘發大幅度的血管放鬆反應。更高的刺激劑劑量,即使會使細胞內鈣離子濃度上升至mM的水準,也不致對血管張力產生額外的影響。若將不同刺激劑所誘導的胞內鈣離子濃度上升與血管張力做比較,會發現血管放鬆程度與鈣離子濃度上升量呈對數正相關。而不同刺激劑所得的結果皆相同,顯示這兩項參數之相關性並無刺激劑專一性的現象。
  此外,當受正腎上腺素前處理過的血管,若浸以去鈣離子的緩衝液,會造成血管內皮細胞鈣離子濃度下降,並引發血管強烈收縮。若以血管放鬆因子的抑制劑做前處理,則發現去鈣離子的緩衝液只會造成鈣離子下降,而無血管再額外收縮的情形產生。顯示鈣離子下降造成基礎血管放鬆因子釋放的減少,是造成血管再額外收縮的主因。當血管以40 mM的鈣離子偶合劑BAPTA前處理時,乙醯膽鹼無法誘發內皮細胞鈣離子上升,也無法使血管放鬆。若血管以20 mM的BAPTA前處理,乙醯膽鹼會造成內皮細胞胞內鈣離子上升約150 nM。然而此條件仍足以造成血管完全放鬆。此結果證明內皮細胞胞內鈣離子在調節血管張力的功能中,扮演統合者的角色。
  綜合本論文發現,內皮細胞胞內鈣離子在血管的分支區有刺激劑專一性的表現,且其表現之樣式、強度也都有區域性的差異。而在功能上,內皮細胞胞內鈣離子又扮演一個統合者的角色。因此在生物個體面臨生理挑戰時,例如運動時,生物體所分泌的內生性物質可能藉由對內皮細胞胞內鈣離子的區域專一性刺激靈敏度的不同而對血流在體內的分布作適當的分配。
 Endothelial cells are heterogeneous in their surface receptors, signaling pathways, intrinsic genetic programs and physiological functions. Microvascular endothelium cultured from the brain, liver and other organs each expresses distinct patterns of cell surface markers, protein transporters, and intracellular enzymes. Many human vascular diseases are restricted to specific types of vessels. More and more evidence have shown that the preferential occurrences of vascular diseases might result from certain molecules expressed at particular endothelium. Although study on the endothelial heterogeneity might provide valuable information on the target specificity and reveal the possible mechanism of the diseases and the selectivity for future vascular therapeutics, the information regarding local endothelial heterogeneity is largely lacking at the present time.

 Since fluid shear stress and vessel thickness change drastically at the intercostal orifice of aorta, endothelial cells surrounding the orifice are exposed to environmental conditions that are locally heterogeneous. The endothelial phenotype of that particular area may be subjected to some modification resulting from intrinsic genetic programs or the adaptation to the environment. It is plausible that the receptor portraits and signaling pathways are modified to some extent in that region. The endothelial cytosolic free Ca2+ concentration (EC [Ca2+]i) signaling is the most common signaling pathway mediating endothelial functions. The phenotypic characteristics might change drastically if EC [Ca2+]i signaling undergoes significant modulations in response to environment challenges. The primary goal of this study was to examine the regional heterogeneous response of endothelial [Ca2+]i signaling in intact rat aortic endothelium.
 
 By studying the endothelial [Ca2+]i signaling in intact rat aorta, the author revealed that there is agonist specific heterogeneous [Ca2+]i signaling in intact rat aortic endothelium. Acetylcholine or histamine reversibly activated the vascular endothelium by eliciting M3 or H1 receptor-mediated [Ca2+]i elevation, respectively. The acetylcholine-evoked endothelial [Ca2+]i elevation at the branch site (intercostal orifice) was much more pronounced than that at the non-branch area. However, endothelium at the branch site was relatively insensitive to histamine. Both acetylcholine-sensitive and histamine-sensitive endothelial cells were arranged in belts aligned along flow lines and were intercalated with each other. Endothelial cells located at the non-branch site showed drastically heterogeneous [Ca2+]i responses to a fixed concentration of either acetylcholine or histamine, differing by two orders of magnitude in individual cells.

 The control of vascular tone by endothelial cells is one of the most important functions of vascular endothelium. Although endothelial derived relaxing factors could be released in a calcium independent manner under some circumstances, the central dogma of endothelial-modulated vasodilatation remains the calcium dependent. In response to various chemical and physical stimuli, an elevation of [Ca2+]i level followed by the activation of calcium-dependent enzymes/channels was observed in most cases. Nevertheless, the quantitative relationship between EC [Ca2+]i and vascular tone remains unclear at present time. Therefore, another specific aim of this thesis was to study the role of EC [Ca2+]i signaling in modulation of vascular tone in rat aortae.

 The role of endothelial [Ca2+]i in regulating vascular tone was examined by using a novel method that allows simultaneous recording of endothelial fura-2 ratio images and vascular displacement in rat aortic segments in a flow system. Since neither endothelial [Ca2+]i elevation nor vasodilatation was observed during or at the onset of flow, the calcium dependent/independent of flow effects was insignificant under our experimental conditions. In an en face preparation pre-contracted with phenylephrine, endothelial [Ca2+]i elevation followed by vasorelaxation was observed upon application of either acetylcholine or ionomycin. Vascular tone was highly sensitive to endothelial [Ca2+]i changes, especially near the basal level; while low doses of agonists induced minor increases of endothelial [Ca2+]i (<200 nM) and concomitant vasorelaxation close to maximal value, high doses of agonists elevated endothelial [Ca2+]i to mM range with small additional vessel dilatation. When endothelial [Ca2+]i was plotted against the vasorelaxation, the curves were almost identical for both acetylcholine and ionomycin treatments. Calcium-free solution reduced basal endothelial [Ca2+]i and induced a concomitant vascular contraction. Although inhibitors for endothelium-dependent relaxing factors did not prevent endothelial [Ca2+]i changes, they abolished both agonist-induced vasodilatation and calcium free solution-induced vessel contraction. While 40 mM BAPTA abolished both agonist-induced endothelial [Ca2+]i elevation and vasodilatation, 20 mM BAPTA prevented the acetylcholine-induced endothelial [Ca2+]i elevation to more than 150 nM without altering the maximal vasodilatation. These results indicate that endothelial [Ca2+]i level seems to serve as an integrating signal in both basal and stimulated states.

 In conclusion, endothelial [Ca2+]i signaling is heterogeneous in the branch area regarding its agonist-specificity, signaling amplitude, and pattern. As EC [Ca2+]i level was an integrating signaling in vasodilatation, the author proposed that there might be an agonist specific regulation of blood distribution especially during stress situation such as exercise.
目錄 Ⅰ
圖表目錄 Ⅲ
中文摘要 1
英文摘要 4
第一章 緒論 7
    內皮細胞的生理功能 7
    內皮細胞間的訊息傳遞 9
    內皮細胞的分化與差異性 11
    細胞胞內鈣離子訊息傳遞 15
    內皮細胞的胞內鈣離子對血管放鬆因子的調控 19
    本論文研究計畫 21
第二章 材料與方法 25
    實驗動物 25
    藥品及溶液之製備 25
    血管之製備 26
    血管段之螢光染色 27
    血管之固定與流體室的組裝 27
    儀器裝置與鈣離子的檢測 28
    ACh與histamine的比值影像之取得 29
    胞內鈣離子濃度之計算 30
    同時定量內皮細胞鈣離子濃度與血管張力 31
    血管張力之計算 32
    血管張力實驗之流程 32
    統計分析 33
第三章 老鼠主動脈內皮細胞鈣離子訊息傳遞之差異性 34
    摘要 34
    前言 35
    結果 38
    討論 42
第四章 老鼠主動脈內皮細胞[Ca2+]i調節整合血管張力 48
    摘要 48
    前言 50
    結果 52
    討論 56
第五章 內皮細胞之區域性差異機轉研究 62
    摘要 62
    前言 63
    實驗設計 66
    結果 68
    討論 71
第六章 總結與討論與未來的發展計畫 74
    本研究之主要成果與總結討論 74
    未來的研究方向 78
參考文獻 80
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