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研究生:陳政男
研究生(外文):Chen Cheng-Nan
論文名稱:分析血管平滑肌細胞型態調節之分子機制及平滑肌細胞在擾流中對於白血球粘黏與橫越內皮細胞移動之影響
論文名稱(外文):Phenotypic Modulation of Vascular Smooth Muscle Cells and Its Contribution to Leukocyte Recruitment to Endothelial Cells under Disturbed Flow
指導教授:裘正健裘正健引用關係
指導教授(外文):Chiu Jeng-Jiann
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:英文
論文頁數:112
中文關鍵詞:擾流橫越內皮細胞移動共培養白血球平滑肌細胞內皮細胞
外文關鍵詞:disturbed flowtransendothelial migrationco-cultureleukocytesmooth muscle cellendothelial cell
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動脈硬化症的形成通常發生於血管分歧或分叉處的擾流(disturbed flow)區域,而形成動脈硬化症的關鍵步驟為動脈血管平滑肌細胞型態改變(phenotypic modulation)以及白血球粘黏(adhesion)至內皮細胞(endothelial cells)且橫越內皮細胞移動(transmigration)。在正常動脈血管中,平滑肌細胞維持收縮型(contractile phenotype)以調控血管彈性及功能。但在動脈硬化症形成時,一旦受到環境中生長因子(growth factors)或細胞激素(cytokines)刺激,型態便會轉變為合成型(synthetic phenotype),此時平滑肌細胞收縮型結構蛋白(如SM-actin、SM-MHC或Calponin)表現量降低,開始增生及發炎,並影響內皮細胞表現粘黏因子(adhesion molecules)或驅化蛋白(chemokines),使白血球黏附並且累積。本論文的主要目的為探討平滑肌細胞受到血小板衍生生長因子(PDGF-BB)與第一型介白素(IL- 1)刺激後,其型態轉變之分子機制,並進而探討不同型態平滑肌細胞在擾流中對於不同白血球[嗜中性球(neutrophils)、淋巴球(PBLs)、單核球(monocytes)]粘黏與橫越內皮細胞移動的影響。
結果發現,平滑肌細胞受到血小板衍生生長因子與第一型介白素同時刺激時,型態會由收縮型轉變為合成型。研究中利用人體主動脈血管平滑肌細胞,將其培養於聚合膠原蛋白(polymerized collagen)上,發現平滑肌細胞收縮型結構蛋白(SM-actin、SM-MHC及calponin)表現量逐漸增加,轉變為收縮型。收縮型的平滑肌細胞若單獨以血小板衍生生長因子或第一型介白素刺激,型態仍維持在收縮型,不會有任何改變。但若同時以血小板衍生生長因子與第一型介白素刺激,則引起平滑肌細胞內PDGFR-、Akt 和p70S6K持續的磷酸化(sustained phosphorylation),進而降低收縮型結構蛋白的表現。加入PI3K抑制劑(wortmannin、LY294002)與mTOR抑制劑(rapamycin)皆會抑制血小板衍生生長因子與第一型介白素所引起的細胞內訊息傳遞,收縮型結構蛋白表現也隨之增加;若將細胞感染帶顯性抑制(dominant-negative) Akt的腺病毒則會抑制PDGF-BB與IL-1引起的p70S6K磷酸化,進而增加收縮型結構蛋白的表現;而感染帶持續活化(constitutively active) Akt腺病毒的細胞則引起與PDGF-BB與IL-1同時刺激時相同的反應,即會活化平滑肌細胞轉變形態成合成型。此外,同時刺激PDGF-BB與IL-1會造成平滑肌細胞內PDGFR-與IL-1R1的連結(association),而這樣的連結會被PDGFR-或IL-1R1的抑制劑或中和抗體(neutralizing antibody)所抑制,並進而抑制PDGFR-、Akt與p70S6K持續的磷酸化,收縮型結構蛋白的表現也會增加。
本研究進而將合成型平滑肌細胞與內皮細胞共培養,觀察不同白血球在擾流中粘黏與橫越內皮細胞移動的情形,結果發現內皮細胞與合成型平滑肌細胞共培養後引起不同的粘黏與驅化蛋白表現量增加,也因此造成大量白血球粘黏與橫越內皮細胞移動。研究中分析此三種白血球在內皮細胞底層的移動特性,發現嗜中性球具有最高之驅動性,可在內皮細胞下快速且無方向性的移動;淋巴球之移動受流場影響最大,幾乎沿著流場方向運動;單核球的移動力(motility)最低,橫越移動至內皮細胞層下後幾乎滯留於平滑肌細胞區;研究中亦分析白血球橫越內皮移動所需時間,發現三種白血球在擾流流場的再黏附區(reattachment area)橫越內皮移動所需時間皆比其他區域少,且不同粘黏因子與驅化蛋白對於不同白血球粘黏、橫越內皮移動的影響程度也不同,若分析內皮細胞與平滑肌細胞內與發炎反應有關的基因及蛋白質表現,本研究發現有3個粘黏因子(ICAM-1, VCAM-1, and E-selectin)和7個驅化蛋白(MCP-1, IL-8, RANTES, GRO-, IP-10, I-TAC, SDF-1)在不同型態白血球遷移機制中扮演不同的調解功能。
本論文的研究結果提供平滑肌細胞在動脈硬化症形成時,受細胞增生因子與發炎因子共同刺激後型態轉變之分子機制。也證明了平滑肌細胞與擾流對於不同型態白血球與血管壁間之交互作用扮演著相當重要的角色。
The early stage of atherogenesis develops at regions of arterial tree exposed to disturbed flow and involves adhesion of leukocytes (WBCs) to and their transmigration across endothelial cells (ECs), which are located in close proximity to smooth muscle cells (SMCs). SMCs located in normal arterial media exhibit a contractile phenotype, whereas SMCs in atherosclerotic plaques show a synthetic phenotype. Growth factor platelet-derived growth factor (PDGF)-BB and cytokine interleukin (IL)-1 contribute to progression of atherosclerotic lesions, where medial vascular SMCs change from their contractile to synthetic phenotype. The aims of this study were (1) to elucidate the role of PDGF-BB and IL-1 in phenotypic modulation of SMCs, and (2) to investigate the effects of disturbed flow and SMCs on the recruitment of three different types of WBCs [neutrophils, peripheral blood lymphocytes (PBLs), and monocytes] to ECs using our newly developed EC/SMC co-culture flow system.
Human aortic SMCs grown on polymerized collagen showed time-dependent increases in the expression of contractile protein markers, including smooth muscle (SM)-actin, myosin heavy chain (SM-MHC), and calponin. Co-stimulation of these SMCs with PDGF-BB and IL-1 induced a sustained phosphorylation of their PDGF receptor (PDGFR)-, Akt and, p70S6K and down-regulated the expression of SM-actin, SM-MHC, and calponin. In contrast, the mTOR inhibitor rapamycin inhibited the PDGF-BB/IL-1-induced p70S6K phosphorylation and elevated these marker protein expressions. While adenoviruses expressing dominant-negative Akt eliminated the PDGF-BB/IL-1 effect on SM- actin, SM-MHC, and calponin expressions, constitutively active Akt mimicked the PDGF-BB/IL-1 effect. PDGF-BB/IL-1 co-stimulation induced a sustained association between PDGFR- and IL-1 receptor (IL-1R1). This receptor association was blocked by a PDGFR- neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), or a specific inhibitor of PDGFR- phosphorylation (AG1295), which consequently eliminated the PDGF-BB/IL-1-induced activation of PDGFR-/Akt/p70S6K and down-regulation of SMC marker protein expressions.
When ECs were co-cultured with synthetic SMCs embedded in the collagen gel, the adhesion and transmigration of neutrophils, PBLs, and monocytes were increased in comparison to the monoculture ECs. Disturbed flow enhanced WBC recruitment to the EC/SMC, particularly in the reattachment area, where the rolling velocity of WBCs and their transmigration time were decreased, as compared with the other areas. Neutrophils, PBLs, and monocytes showed different subendothelial migration patterns under disturbed flow. Their movements were more random and shorter in distance in the reattachment area. Co-culture of ECs and SMCs induced their expressions of adhesion molecules and chemokines, which contributed to the increased WBC adhesion and transmigration.
Our findings indicate that ECM components play an important role in the control of phenotypic properties of cultured SMCs. The findings also provide insights into the mechanisms contributing to phenotypic change of SMCs from contractile to synthetic state. Since SMCs in the plaques exert significant effects on ECs, the results from the use of our newly developed EC/SMC co-culture model may provide data for the understanding of the interaction between WBCs and the vessel wall (composed of ECs and SMCs) under the complex flow environments found in regions of prevalence of atherosclerotic lesions.
Chapter I. Introduction1
1.1. The Pathogenesis of Atherosclerosis2
1.2. Cellular Components of Atherosclerosis3
1.3. Hemodynamic Factors in Atherosclerosis4
1.4. Endothelial Cell Functions and Atherosclerosis6
1.5. Phenotypic Modulation of Vascular Smooth Muscle Cells7
1.6. WBC Adhesion and Transmigration9
1.7. The Aims of the Study11
Chapter II. Materials and Methods15
2.1. Materials16
2.1.1. Cells16
2.1.2. Medium16
2.1.3. Antibodies16
2.1.4. Chemicals and Reagents17
2.1.5. Buffers17
2.2. Protocols Used for Studying Synergistic Roles of PDGF-BB and IL-1 in Phenotypic Modulation of Human Aortic SMCs18
2.2.1. Collagen Substrates18
2.2.2. Experimental Procedures for Studying SMC Phenotypic Modulation19
2.2.3. Western Blot Analysis19
2.2.4. Electrophoretic Mobility Shift Assay (EMSA) 20
2.2.5. Adenoviral Infection20
2.2.6. BrdUrd Incorporation Assay21
2.2.7. Immunoprecipitation21
2.3. Protocols Used for Studying the Adhesion, Transmigration, and Subendothelial Migration of Neutrophils, Lymphocytes, and Monocytes in the EC/SMC Co-culture under Disturbed Flow22
2.3.1. Flow System and Chamber Design22
2.3.2. EC Culture22
2.3.3. Neutrophils Isolation23
2.3.4. PBLs Isolation23
2.3.5. Monocytes Isolation23
2.3.6. Co-culture Model24
2.3.7. Adhesion and Transmigration Assays24
2.3.8. RNA Isolation25
2.3.9. RT-PCR26
2.3.10. Flow Cytometry26
2.3.11. Enzyme-Linked Immunosorbent Assay (ELISA) 27
2.3.12. Statistical Analysis27
Chapter III. Results31
3.1. Synergistic Roles of PDGF-BB and IL-1 in Phenotypic Modulation of Human Aortic SMCs32
3.1.1. PDGF-BB and IL-1 Synergistically Induce Contractile-to-Synthetic Phenotypic Modulation of SMCs Cultured on Polymerized Collagen32
3.1.2. PDGF-BB/IL-1-Induced Phenotypic Modulation of SMCs on Polymerized Collagen is Mediated by the PI3K/Akt/p70S6K Pathway33
3.1.3. PDGF-BB/IL-1 Induce a Sustained Phosphorylation of PDGFR- and Its Association with IL-1R1 in SMCs on Polymerized Collagen34
3.1.4. Sustained Phosphorylation of PDGFR- and Its Association with IL-1R1 Are Required for the PDGF-BB/IL-1-Induced Activation of Akt and p70S6K and Phenotypic Modulation of SMCs on Polymerized Collagen35
3.1.5. PDGF-BB/IL-1 Inhibited Polymerized Collagen-Induced SRF-DNA Binding Activity in SMCs through PDGFR-/IL-1R1 Association and the PI3K/Akt/p70S6K Pathway36
3.2. Neutrophils, Lymphocytes, and Monocytes Exhibit Diverse Behaviors in Transendothelial and Subendothelial Migrations under Co-culture with SMCs in Disturbed Flow37
3.2.1. ECs Co-cultured with SMCs Showed Increases in Neutrophil, PBL, and Monocyte Adhesion and Transmigration under Disturbed Flow, Especially in the Vicinity of Flow Reattachment37
3.2.2. Reattachment Flow Decreases the Velocity of Rolling and the Transendothelial Migration Time of Neutrophils, PBLs, and Monocytes Adherent to ECs Co-cultured with SMCs38
3.2.3. Neutrophils, PBLs, and Monocytes Show Differential Patterns of Migration Beneath the EC Monolayers under Disturbed Flow38
3.2.4. Co-culture of ECs and SMCs Induces Their Expression of Several Adhesion Molecules and Chemokines Relevant to WBC Recruitment39
3.2.5. Contributions of Adhesion Molecules and Chemokines to the Adhesion of Neutrophils, PBLs, and Monocytes to ECs and Their Subsequent Migrations Across and Beneath the ECs Co-cultured with SMCs Under Disturbed Flow40
Chapter IV. Discussion78
4.1. PDGF-BB/IL-1 Co-stimulation of SMCs Grown on Polymerized Collagen Induces Their Phenotypic Modulation from a Contractile to a Synthetic Phenotype, and This Phenotypic Modulation is Mediated by the Phosphorylation of PDGFR- and Its Association with IL-1R1 and through the PI3K/Akt/p70S6K Pathway79
4.2. Roles of Sustained Phosphorylation of PDGFR- and Its Association with IL-1R1 upon PDGF-BB/IL-1 Co-stimulation80
4.3. SRF-CArG Binding Activity is Regulated by PDGFR-/IL-1R1 Association and PI3K/Akt/p70S6K Pathway83
4.4. SMCs in a Synthetic Phenotype Increase WBC Recruitment to ECs84
4.5. Disturbed Flow Increases WBC Recruitment to ECs84
4.6. Neutrophils, PBLs, and Monocytes Show Differential Migration Patterns Underneath ECs85
4.7. Effects of Adhesion Molecules and Chemokines Produced by ECs and SMCs in Their Co-culture on WBC Recruitment86
4.8. Implication90
4.9. Future Directions92
4.10. Summary94
Chapter V. Conclusion97
References99
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