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系統識別號 U0026-1606201400271200
論文名稱(中文) 探討alpha-MSH在內皮細胞中的作用與其訊息傳遞調控路徑
論文名稱(英文) The Regulatory Functions and Signaling Pathways of Alpha- Melanocyte-Stimulating Hormone in Endothelial Cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 翁汶燦
研究生(英文) Wen-Tsan Weng
電子信箱 bppig@yahoo.com.tw
學號 S58931031
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-吳昭良
共同指導教授-戴明泓
召集委員-吳梨華
口試委員-吳華林
口試委員-洪文俊
口試委員-華瑜
口試委員-王逢興
中文關鍵字 alpha-黑色素細胞刺激素  內皮細胞  血管新生  血管內皮生長因子  一氧化氮  黑皮質素接受器  通透性 
英文關鍵字 alpha-melanocyte-stimulating hormone  endothelial cells  angiogenesis  vascular endothelial growth factor  nitric oxide  melanocortin receptor  permeability 
學科別分類
中文摘要 alpha-黑色素細胞刺激素 (alpha-MSH) 是從proopiomelanocortin (POMC) 衍生所得到的胜肽。除了最常見的色素調節作用外,alpha-黑色素細胞刺激素也具有顯著地抗發炎和免疫調節的功能。然而,alpha-黑色素細胞刺激素及其受體在內皮細胞中所扮演的角色與作用仍然是未知的。之前我們已經觀察到利用POMC做基因治療不僅能減少腫瘤中血管新生的現象,也可以在骨關節炎的大鼠動物模式中抑制其新生血管的生成。而我們發現了alpha-黑色素細胞刺激素似乎參與了POMC所造成的抑制血管新生的作用。此外,POMC也能有效地減少內皮細胞間隙形成,已知內皮細胞間隙形成與否會影響內皮細胞的血管新生作用和其血管通透性。因此,我們推測alpha-黑色素細胞刺激素可能在調控內皮細胞血管新生與其通透性上扮演著重要的角色。在本研究中,我們發現alpha-黑色素細胞刺激素能在活體實驗中觀察到其具有抑制新生血管生成的能力;而在利用人類臍帶靜脈內皮細胞所做的研究中,我們發現alpha-黑色素細胞刺激素雖然對於內皮細胞的增生能力影響並不顯著,但是alpha-黑色素細胞刺激素能夠明顯地抑制內皮細胞基質金屬蛋白酶2的分泌、內皮細胞的遷移與內皮細胞形成管狀構造的能力;因此,我們證實了alpha-黑色素細胞刺激素能夠抑制血管新生過程中內皮細胞的許多作用。我們進一步釐清了alpha-黑色素細胞刺激素會抑制內皮細胞中血管內皮生長因子和血管內皮生長因子接受器2的表現。另外,我們還觀察到alpha-黑色素細胞刺激素也能減少內皮細胞中一氧化氮的生成;此抑制一氧化氮生成的作用主要是alpha-黑色素細胞刺激素減少了內皮細胞中內皮型一氧化氮合成酶的表現與活性,以及透過抑制內皮細胞內NFκB的活化而達到抑制誘發型一氧化氮合酶的表現。同時,我們發現了在常見的5個黑皮質素接受器中,內皮細胞具有黑皮質素-1、2、4與5接受器的存在;而alpha-黑色素細胞刺激素在內皮細胞中抑制血管新生的作用,主要是藉由活化黑皮質素-1接受器和黑皮質素-2接受器,進而去抑制血管內皮生長因子/血管內皮生長因子接受器2與一氧化氮合成酶的表現與其訊息傳遞。除了在內皮細胞的血管新生作用外,我們發現alpha-黑色素細胞刺激素也能顯著地減少內皮細胞的通透性。alpha-黑色素細胞刺激素可以抑制內皮細胞在缺氧狀態下所誘發的血管內皮生長因子、血管內皮生長因子接受器2、內皮型一氧化氮合成酶、誘發型一氧化氮合酶與改變內皮細胞彼此間組成緊密連接分子的形成。總結以上的發現,我們是最早提出充分的證據去證實了alpha-黑色素細胞刺激素具有抑制內皮細胞血管新生與血管通透性的能力。我們的實驗結果對於POMC誘發血管新生抑制的相關機轉提供了一個線索與新的認識;這些新的發現或許能有助於alpha-黑色素細胞刺激素與黑皮質素接受器將來在內皮細胞的血管新生作用調控與缺血性中風的治療上有更進一步的治療策略。
英文摘要 alpha-melanocyte-stimulating hormone (alpha-MSH) derived from proopiomelanocortin (POMC) is well known to be a pigment-inducing peptide, as well as has potent anti-inflammatory and immunomodulatory properties. However, the biological roles of alpha-MSH and its receptors in endothelial functions remain elusive. We have previously observed that POMC gene delivery reduces tumor angiogenesis and also inhibits vascularization in rat model of osteoarthritis. We also find that alpha-MSH seems to participate in the POMC-mediated anti-angiogenesis. Besides, POMC potently reduces the endothelial gap formation which involved in endothelial angiogenesis and permeability. Therefore, we speculated that alpha-MSH played an important role in endothelial functions, especially angiogenesis and permeability. In this study, we found that alpha-MSH not only suppressed angiogenesis in vivo but also inhibited multiple angiogenic progresses including matrix metalloproteinase-2 secretion, migration and tube formation of HUVECs without affecting proliferation. We further clarified that alpha-MSH repressed vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expressions in endothelial cells. Besides, we also observed that alpha-MSH also decreased the nitric oxide (NO) production. The down-regulation of NO production mediated by alpha-MSH were through reducing eNOS expression and activities, as well as inhibiting NFκB activities that attenuated iNOS expression in endothelial cells. We also found the expression of melanocortin-1 receptor (MC-1R), MC2-R, MC-4R and MC5-R, but not MC3-R, in endothelial cells. The antiangiogenic effects of alpha-MSH were through activating MC-1R and MC2-R that blocked VEGF/VEGFR2 and NOSs signaling in endothelial cells. In addition to endothelial angiogenesis, we found that alpha-MSH significantly repressed the endothelial permeability under normal conditions or hypoxia. alpha-MSH also inhibited VEGF, VEGFR2, eNOS and iNOS expression, as well as changed endothelial tight junction formation in endothelial cells exposed to hypoxia. Collectively, we first unveiled the inhibitory functions of alpha-MSH on angiogenesis and permeability in endothelial cells. Our experimental results also shed a new light of molecular mechanisms underlying the inhibition of POMC-mediated angiogenesis. These emerging finding highlight therapeutic strategy of alpha-MSH and receptors for alleviation of endothelial angiogenesis and ischemic stroke.
論文目次 Index
Abstract in Chinese 1
Abstract in English 3
Acknowledgement 5
Index 7
Figure Index 11
Abbreviations 13
Chapter I. Introduction 15
1.1 Pro-opiomelanocortin (POMC) 16
1.2 Melanocortins 17
1.3 alpha-melanocortin-stimulaing hormone (alpha-MSH) 20
1.4 Angiogenesis 23
1.5 Vascular endothelial growth factor (VEGF) 24
1.6 Nitric oxide (NO) 27
1.7 Specific aims 29

Chapter II. Materials and Methods 31
2.1 Peptides and antibodies 32
2.2 Animal care 32
2.3 Endothelial cells cultures 32
2.4 Aortic ring assay 33
2.5 Angiogenesis in zebrafish model 34
2.6 Chick chorioallantoic membrane (CAM) assay 34
2.7 Cell viability assay 35
2.8 Gelatin zymography 35
2.9 Scratch wound healing assay 35
2.10 Boyden chamber assay 36
2.11 Tube formation assay 36
2.12 Immunofluorescence assay 37
2.13 Flow cytometry analysis 37
2.14 Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) 38
2.15 Western blot analysis 38
2.16 Enzyme-linked immunosorbent assay (ELISA) 39
2.17 Measurement of cAMP 39
2.18 Nitric oxide measurement 40
2.19 NFκB activity assay 40
2.20 Hypoxic conditions 40
2.21 Endothelial permeability assay 40
2.22 Statistical analysis 41

Chapter III. The Effects of Alpha-MSH on VEGF/VEGFR2 Signaling in Endothelial Cells 42
3.1 Abstract 43
3.2 Introduction 44
3.3 Results 46
3.3.1 alpha-MSH perturbed angiogenesis ex vivo and in vivo
46
3.3.2 alpha-MSH suppressed multiple angiogenic processes in endothelial cells 46
3.3.3 alpha-MSH reduced VEGF expression in endothelial cells at transcriptional level 47
3.3.4 alpha-MSH attenuated the VEGFR2 expression and Akt phosphorylation but elevated PTEN protein level in endothelial cells 47
3.3.5 MC1-R and MC2-R were involved in alpha-MSH-induced inhibition of angiogenesis in endothelial cells 48
3.3.6 Excessive VEGF supply failed to restore the alpha-MSH-induced inhibition of angiogenesis 49
3.4 Discussion 50
3.5 Figure and legends 53

Chapter IV. The Roles of Alpha-MSH in Endothelial NO Bioavailability 65
4.1 Abstract 66
4.2 Introduction 67
4.3 Results 70
4.3.1 alpha-MSH decreased NO production and eNOS activation in endothelial cells 70
4.3.2 alpha-MSH inhibited iNOS expression in endothelial cells via downregulation of NFκB activities 70
4.3.3 MC1-R and MC2-R contributed to alpha-MSH-induced NOSs inhibition in endothelial cells 71
4.3.4 cAMP/PKA signaling was required for alpha-MSH-mediated eNOS and iNOS expression in endothelial cells 72
4.3.5 Application of NO donor, L-arginine, restored the NOSs expression and angiogenic functions in alpha-MSH-treated endothelial cells 72
4.3.6 L-arginine supply reversed the alpha-MSH-induced angiogenesis inhibition in vivo 73
4.4 Discussion 74
4.5 Figure and legends 78


Chapter V. The Effects of Alpha-MSH on Endothelial Permeability 88
5.1 Abstract 89
5.2 Introduction 90
5.3 Results 93
5.3.1 alpha-MSH inhibited the hyper-permeability in CoCl2- treated and hypoxia-treated endothelial cells 93
5.3.2 alpha-MSH inhibited the CoCl2-induced VEGF and VEGFR2 expression in endothelial cells 93
5.3.3 alpha-MSH inhibited the CoCl2-induced eNOS and iNOS expression in endothelial cells 94
5.3.4 alpha-MSH promoted tight junctions formation but repressed adherens junctions formation in endothelial cells under hypoxia 94
5.4 Discussion 95
5.5 Figure and legends 98

Chapter VI. Conclusions and Future Perspectives 103
6.1 Conclusions 104
6.2 Future perspectives 106
6.3 Figures and legends 109

References 110
Appendix 123
Publications 126
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