平滑肌收縮是藉由細胞內鈣離子的增加及收縮器對鈣離子的敏感化所調控。細胞內鈣離子增加活化了Ca2+/Calmodulin依賴性的肌凝蛋白輕鏈激酶(MLCK) ，而鈣離子的敏感化主要是藉由抑制肌凝蛋白輕鏈去磷酸酶（MLCP）。本研究的主題即利用大白鼠尾動脈做為模式來探討a1腎上腺素受體致效劑phenylephrine (PE) 及thromboxane A2 類似物U46619所引發的平滑肌收縮的訊息傳遞路徑。首先，我們針對胞外訊息調控蛋白激酶(ERK1/2)在兩種受體致效劑所引發的細胞內鈣離子濃度的變化、鈣離子敏感化及肌凝蛋白輕鏈磷酸化等過程中所扮演的角色做一探討。實驗結果顯示在完整的血管肌束，ERK1/2主要是調控鈣離子敏感化。此外，ERK1/2調控鈣離子敏感化並不經由改變肌凝蛋白輕鏈磷酸化。而PE及U46619活化ERK1/2的過程中並不經由Rho kinase及 genistein-sensitive之酪胺酸激酶。
本論文第二部分的目的是藉由抑制Rho-kinase對PE及U46619所引發的血管平滑肌收縮過程中MYPT1Thr697 /Thr855 或CPI-17Thr38磷酸化的時程及肌動蛋白聚合的影響來釐清MYPT1 或CPI-17的磷酸化以及肌動蛋白的聚合在Rho-kinase所主導的平滑肌收縮中的相對角色。Rho-kinase抑制劑Y-27632抑制PE或U46619刺激所產生的收縮力同時伴隨著降低肌凝蛋白輕鏈的磷酸化。PE或U46619的刺激皆明顯的增加MYPT1Thr855的磷酸化，且此反應可藉由Y-27632的前處理而完全的被抑制。MYPT1Thr697的磷酸化則不受兩致效劑的刺激而增加亦不被Y-27632所抑制。此外，PE而非U46619短暫性的明顯增加CPI-17Thr38的磷酸化，此現象並不受Y-27632的抑制。另一方面，此兩種受體致效劑皆明顯的增加肌動蛋白的聚合，但此現象僅在PE處理組可被Y-27632所抑制。本實驗結果顯示在PE或U46619所引發的血管平滑肌收縮過程中MYPT1Thr855及肌凝蛋白輕鏈的磷酸化以及收縮力三者之間在時間上具相關性，而且Rho-kinase是經由磷酸化MYPT1Thr855來調控MLCP的活性。此外，Rho-kinase可調控由a1腎上腺素受體活化，而非TXA2受體活化所誘導的肌動蛋白聚合作用。
本論文第三部分的目的便是探討NADPH oxidase所產生的活性氧物質在a1腎上腺素受體致效劑PE所引發的血管平滑肌收縮所扮演的角色。我們發現兩種作用機制不同的NADPH oxidase抑制劑DPI 及apocynin呈劑量相依性的抑制PE所引發的收縮。利用化學冷光分析可觀察到PE刺激可促使大白鼠尾動脈超氧陰離子的生成增加，此反應可被a1腎上腺素受體拮抗劑prazosin，apocynin及trion所抑制，但不受xanthine oxidase抑制劑 allopurinol或環氧化酶抑制劑indomethacin的影響。更進一步分析NADPH oxidase活性的結果顯示，PE刺激1分鐘後確實明顯增加了該酵素的活性，且該反應受到DPI 及apocynin的抑制但不受allopurinol或rotenone的影響。此外，PE刺激肌凝蛋白輕鏈的磷酸化在收縮起始期呈劑量相依性地為DPI 及apocynin所抑制，但在平穩期僅受apocynin的抑制。同樣的抑制效果在PE刺激MYPT1Thr855磷酸化亦可觀察到。該兩種抑制劑也顯著的抑制由PE所引發的RhoA活化及CPI-17Thr38磷酸化。這些結果強烈顯示a1腎上腺素受體的活化刺激NADPH oxidase產生活性氧物質，透過Rho/Rho-kinase將MYPT1Thr855殘基磷酸化以及CPI-17兩訊息傳遞路徑抑制肌凝蛋白輕鏈去磷酸酶的活性，進而增加肌凝蛋白輕鏈磷酸化的程度來促成血管平滑肌的收縮。綜合本論文的成果我們對血管平滑肌興奮-收縮聯結提供一新的分子調控機轉，而此調控機制的失常可能會導致一些臨床病癥如高血壓或血管痙癴等。因此能對血管收縮的分子機轉有進一步的瞭解將有助於吾人在未來抗高血壓藥物的研發上提供新的標靶。

Smooth muscle contraction is regulated by increase in cytoplsmic Ca2+ and Ca2+ sensitivity of the contractile apparatus. The former activates myosin light chain kinase (MLCK) whereas the later mainly involves the inhibition of myosin light chain phosphatase (MLCP). In this study, the signaling mechanisms involved in the regulation of contraction activated by a1-adrenoceptor (a1-AR) agonsit phenylephrine (PE) and thromboxane A2 (TXA2) mimetic U46619 in rat tail artery (RTA) were investigated. The first part of this thesis explored the roles of extracellular signal-regulated kinase 1/2 (ERK1/2) in modulating [Ca2+]i, Ca2+ senstivity and MLC20 phosphorylation activated by both agonists. The results indicated that ERK1/2 modulate mainly Ca2+ sensitivity and, to a smaller extent, Ca2+ mobilization in smooth muscle contraction. In addition, ERK1/2 does not modulate Ca2+ sensitivity through changes in MLC20 phosphorylation. Furthermore, ERK1/2 activation induced by either agonist does not involve Rho-kinase or genistein-sensitive tyrosine kinases in RTA.
The second part of this thesis was aimed to clarify the relative contribution of MYPT1 and CPI-17 phosphorylation, as well as actin polymerization in Rho kinase-mediated contraction. The effects of Rho kinase inhibition on the time course of MLCP subunit MYPT1 phosphorylation at Thr697 and Thr855, CPI-17 phosphorylation at Thr38, and on actin polymerization during vasocontraction were examined. Rho-kinase inhibitor Y27632 suppressed force activated by PE or U46619 with concomitant decreases in MLC20 phosphorylation. Both agonists significantly increased MYPT1Thr855 phosphorylation that was abolished by Y27632 pretreatment but not MYPT1Thr697 phosphorylation. PE, but not U46619, transiently increased CPI-17Thr38 phosphorylation that was not inhibited by Y27632 but was abolished by a protein kinase C inhibitor. Both agonists increased actin polymerization that was attenuated by Y27632 under PE but not U46619 stimulation. These results demonstrated a temporal correlation between MYPT1Thr855 phosphorylation, MLC20 phosphorylation and contraction in a Rho-kinase-dependent manner for both agonists stimulation, suggesting that Rho-kinase regulates MLCP activity through MYPT1Thr855 phosphorylation during RTA smooth muscle contraction. Moreover, Rho-kinase regulates actin polymerization activated by a1-AR but not TXA2 receptor stimulation.
The third part of this thesis examined the role of NADPH oxidase-derived reactive oxygen species (ROS) in PE-induced contraction. Two different NADPH oxidase inhibitors, DPI and apocynin, dose-dependently inhibited PE-activated force. Using lucigenin-enhanced chemiluminescence assay, PE stimulated superoxide production, which was abolished by the pretreatment of a selective a1-AR antagonist prazosin, apocynin or superoxide scavenger tiron, but not by allopurinol or indomethacin. Concurrently, NADPH oxidase activity increased within 1 min upon PE treatment and was reduced by DPI and apocynin, but not by allopurinol or rotenone. Furthermore, MLC20 phosphorylation was dose-dependently decreased by apocynin and DPI at initial phase and by apocynin at sustained phase. Similar pattern was observed in MYPT1Thr855 phosphorylation. Finally, RhoA activation and the phosphorylation of MLCP inhibitor CPI-17 induced by PE were prevented by NADPH oxidase inhibition. This finding offers a new concept that NAD(P)H oxidase-derived ROS regulate a1-AR-activated vasoconstriction by, at least in part, modulating MLCP-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways. In summary, results from this thesis provide new insight into the molecular mechanisms by which vasoconstrictors evoke smooth muscle contraction, and may help to better evaluate the potential targets for future antihypertensive therapy.

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