摘要
第一部分建立家兔颈总动脉内膜球囊剥脱损伤后新生内膜增殖和血管重塑动态变化模型
目的：目前普遍认为，血管内皮损伤诱发的血管平滑肌细胞(vascular smooth muscle cell，VSMC)增殖并且向内膜迁移，随之引起的内膜增殖和血管重塑被认为是经皮冠状动脉腔内成形术(percutaneous transluminal coronary angioplasty，PTCA)后再狭窄(restenosis，RS)的主要病理机制。为探索RS的发病机制并进行干预研究，我们模拟复制家兔颈总动脉内膜损伤后不同时间点的VSMC增殖和血管重塑动态变化模型。
方法：选用家兔42只行左侧颈总动脉内膜(内皮细胞)球囊剥脱损伤，分别于损伤后1天(day，d)、3d、5d、7d、14d、28d、35d处死家兔，取损伤区域的血管段制备标本HE染色，进行形态学观察。同时应用医学图文分析系统测算损伤后不同时间点各组血管腔面积(lumen area，LA)、内膜和中膜厚度及面积、以及外弹力膜内横截面积(external elastic lamina area，EELA)与对侧未损伤血管比较。
结果：
(1)未损伤侧家兔颈总动脉内膜仅见单层内皮细胞；球囊损伤后1d可见动脉内皮剥脱，损伤后3d血管腔内表面可见增殖的VSMC，损伤后5～7d新生内膜(neointima，NI)形成并逐渐增厚，损伤14d以后NI厚度及面积继续增加，至35d达最大，同时细胞外基质(extracellular matrix，ECM)也逐渐增加。
(2)损伤后3～14d中膜厚度及面积逐渐增加，其中14d中膜面积明显大于未损伤侧，28～35d趋于降低。LA于损伤后5～7d开始减少；14d以后明显小于未损伤侧。损伤后1～7d EELA逐渐增大，至14d达最大，28d后开始回缩。
结论：
(1)家兔颈总动脉内膜球囊损伤能较好的模拟RS形成过程，我们模拟复制的RS动态变化模型是成功的，具有合理性和科学性。
(2)内膜增殖与血管重塑均是RS形成的主要病理机制，RS形成由内膜增殖与血管重塑的失衡所决定，两者协同导致管腔狭窄。
第二部分
实验一动脉内膜损伤后VSMC表型转化及P38 MAPK、MKP-1的表达变化
目的：观察动脉内膜损伤后血管平滑肌细胞(VSMC)表型转化和P38丝裂原激活蛋白激酶(P38 MAPK)、丝裂原激活蛋白激酶磷酸酶-1(MKP-1)表达变化以及它们之间的关系。
方法：本实验通过建立家兔颈总动脉内膜球囊损伤后再狭窄(restenosis，RS)模型，分别应用免疫组化、免疫印迹(Western blot)和逆转录-聚合酶链反应(RT-PCR)方法检测假损伤组(S组)和损伤后不同时间点血管壁中增殖细胞核抗原(PCNA)、平滑肌α肌动蛋白(SMα-actin)、P38 MAPK蛋白和MKP-1蛋白及其mRNA表达的变化。
结果：
(1) S组中膜VSMC及内皮细胞(内膜)PCNA免疫组化染色为阴性；中膜于损伤后1～14d、新生内膜(niointima，NI)于损伤后5～14d PCNA阳性细胞率逐渐增加，以14d达到高峰，28d后开始逐渐减少，但其阳性细胞率仍较高，且各时间点NI中的PCNA阳性细胞率略高于中膜。
(2) S组中膜SMα-actin染色为阳性，内膜为阴性；中膜SMα-actin阳性表达面积于损伤后1d开始减少，3d最为明显，5d后开始逐渐增加，28d后接近于S组水平。损伤后5～35d NI中SMα-actin均有阳性表达，但阳性表达面积略少于中膜。
(3) S组中膜P38 MAPK免疫组化染色呈阴性或弱阳性。中膜于损伤后1～14d、NI于损伤后5～14d P38 MAPK阳性表达面积显著增加，以14d达高峰，28d后开始逐渐减少，但至损伤后35d仍明显高于S组，且NI阳性表达面积高于中膜。Western blot检测损伤后1～35d血管壁中P38 MAPK呈持续性高表达，其中以14d升高最为明显，28d后开始逐渐减少。P38 MAPK与PCNA表达变化呈正相关。
(4) S组中膜及内膜MKP-1免疫组化染色呈弱阳性或阳性。损伤后1～3d中膜阳性表达面积进行性减少，5～7d达到最低值，同时NI呈阴性或弱阳性着色。而损伤后14～28d中膜和NI中MKP-1阳性表达面积略有回升，至35d仍远未回到S组水平，且NI阳性表达面积稍低于中膜。血管壁中MKP-1 mRNA表达变化与其免疫组化结果基本一致，与PCNA表达变化呈负相关。
结论：
(1) VSMC增殖能力与其表型转化密切相关。
(2) P38 MAPK和MKP-1可能参与了血管内膜损伤后VSMC表型转化的信号转导及其调节。
第二部分
实验二粉防己碱对血管内膜损伤后VSMC表型转化和P38 MAPK、MKP-1表达的影响
目的：探讨粉防己碱(tetrandrine，Tet)对血管内膜损伤后血管平滑肌细胞(VSMC)表型转化和P38丝裂原激活蛋白激酶(P38 MAPK)及丝裂原激活蛋白激酶磷酸酶-1(MKP-1)表达的影响。
方法：本实验通过建立家兔颈总动脉内膜球囊损伤模型，采用HE染色检测28天(day，d)假损伤组(sham-injured group，S组)、损伤组(injured group，Ⅰ组)和损伤+Tet治疗组(injured+Tet-treated group，Tet组)血管形态学改变；又分别使用免疫组化、Western blot和RT-PCR技术检测Ⅰ组和Tet组7d、14d和28d血管壁中增殖细胞核抗原(PCNA)、平滑肌α-肌动蛋白(SMα-actin)、P38 MAPK和MKP-1表达的变化。
结果：
(1) S组28d血管壁各层结构完整；Ⅰ组28d新生内膜面积(neointima area，NIA)显著增加，管腔面积(Lumen area，LA)显著缩小；而Tet组新生内膜增殖程度较同期Ⅰ组明显减轻，LA显著增加。
(2)损伤后7d，Tet组与Ⅰ组比较血管壁中的SMα-actin、PCNA、P38 MAPK和MKP-1表达基本一致，新生内膜增殖程度亦基本相同。Tet组14d和28d，血管壁中的PCNA和P38 MAPK表达均分别显著低于同期Ⅰ组，而MKP-1表达均分别显著高于同期Ⅰ组，且Tet对上述各指标的影响均呈时间依赖性；损伤后14、28d SMα-actin表达均略高于同期Ⅰ组。
结论：Tet能够不同程度地拮抗内膜损伤后P38 MAPK信号转导途径及其上调MKP-1的负性调节，抑制VSMC表型转化，继而减缓新生内膜增殖。
第三部分血管内膜损伤后MMP9和TIMP2表达变化及Tet对其表达的影响
目的：探讨血管内膜损伤后基质金属蛋白酶9(matrix metalloproteinases 9，MMP 9)和基质金属蛋白酶抑制剂2(tissue inhibitors of metalloproteinases 2，TIMP 2)在再狭窄细胞外基质(extracellular matrix，ECM)形成中的作用以及粉防己碱(Tetrandrine，Tet)对MMP9、TIMP2表达和新生内膜增殖的影响。
方法：制作家兔颈总动脉内膜损伤后血管再狭窄模型，采用免疫组化、逆转录—聚合酶链反应(RT-PCR)和免疫印迹(Western blot)技术，分别检测假损伤组(S组)28 d时和损伤组(Ⅰ组)、损伤+Tet治疗组(Tet组)7 d、14 d、28 d时血管壁中的MMP9、TIMP2 mRNA及其蛋白表达的变化，以及新生内膜增殖的变化。
结果：
(1)损伤后7 d组血管中膜MMP9阳性表达面积较高，而14和28 d开始逐渐减少；新生内膜于损伤后7 d时MMP9阳性表达面积较低，14 d显著增加，而28d又明显减少。损伤7 d组中膜、新生内膜TIMP2阳性表达面积较低，而14 d和28 d均显著增加。
(2)与同期Ⅰ组比较，Tet组7 d中膜及新生内膜中MMP9和TIMP2阳性表达面积无明显变化，而14 d和28 d两者阳性表达面积均分别显著减少，新生内膜增殖程度也有减轻和明显减轻。
(3)S组动脉壁中MMP9 mRNA及其蛋白水平呈低表达，而TIMP2 mRNA及其蛋白则呈高表达。与S组比较，Ⅰ组7、14和28 d血管壁中MMP9 mRNA和蛋白呈强表达或高表达；Ⅰ组7 d血管壁中TIMP2 mRNA和蛋白呈低表达，而14和28 d又恢复甚至高于S组水平。
(4)与同期Ⅰ组比较，Tet组7 d血管壁中MMP9、TIMP2 mRNA和蛋白表达均无显著变化；而治疗后14和28 d均分别显著减少，以TIMP2 mRNA及其蛋白减少更为明显。
结论：
(1)MMP9和TIMP2不平衡增加和／或比例失衡在血管内膜损伤后ECM形成中具有重要作用。
(2)Tet可降低内膜损伤后血管壁中MMP9和TIMP2 mRNA及其蛋白的异常高表达，使二者比例趋向平衡，减少ECM大量分泌和积累，从而抑制新生内膜增厚和血管重塑。
Part I
Dynamic Model of Neointimal Proliferation and Remodeling of Vascular Wall after Balloon Intimal Injury of Rabbit Carotid Common Arteries
Objective: At present, many studies have reported that proliferation and migration of vascular smooth muscle cell ( VSMC ) in the media, and subsequent neointimal hyperplasia and remodeling of vascular wall is a major pathologic mechanism of vascular restenosis after injury of endothelial cells (intima ) resulted from percutaneous transluminal coronary angioplasty ( PTCA ). To study the mechanism of restenosis for the prevention and treatment following PTCA, we replicated the dynamic models of cellular proliferation and vascular remodeling after intimal denudation of rabbit carotid common arteries at different time points.
Methods: The intima of left carotid common arteries in 42 rabbits was denudated by balloon injury. Rabbits were respectively killed after injury at different time points ( 1 d, 3d, 5 d, 7d, 14d, 28 d and 35 d ). The injured sections were taken out and made into specimens for HE staining. Morphological change of the arterial wall in injury sides and non-injury sides at different time points was observed by microscopy. In addition, Lumen area, thickness and area of the intima and the media, and cross-sectional area bounded by the external elastic lamina ( EELA) in injury sides and non-injury sides at different time points were measured by computer image analysis technology.
Results: (1) Single layer endothelium was only showed in non-injury side arteries at different time points. Endothelial cells were denudated at day 1 after balloon injury. The proliferating of VSMC was spotted on the surface of lumen at 3 days after balloon injury. The neointima had been formed and continuously thicken at 5 ～7 days after injury. The neointimal thickness and area as well as extracellular matrix were gradually increased after 14 days, and they were maximal at 35 days. (2) The thickness and area of the media were gradually increased during 3-14 days, in which the medial area significantly increased at 14 days compared with non-injured vessel, and decreased after 28 days. Lumen area initially decreased at 5 ~ 7 days after injury. Lumen area after 14 days was significantly less than that of non-injured vessel. EELA gradually slightly increased at 1 ~ 7 days after injury, it was maximal at 14 days, but it declined gradually after 28 days.
Conclusion: The models of vascular restenosis established by balloon intimal injury of rabbit carotid common arteries were successfully replicated, and proved to be rational and scientific. Intimal proliferation and vascular remodeling are important pathologic pathogenesis of vascular restenosis. The formation of vascular restenosis was determined by the unbalance of intimal proliferation and vascular remodeling. The both together resulted in lumen narrowing .
Part II Experiment I
Change of P38 MAKP and MKP-1 in Phenotypic Modulation of Vascular Smooth Muscle Cells after Intimal Injury
Objective: To explore relationship among phenotypic modulation of vascular smooth muscle cell ( VSMC ) and change of P38 mitogen-activated protein kinase ( P38 MAPK ) as well as mitogen-activated protein kinase phosphatase-1 ( MKP-1 ) after vascular intimal injury.
Methods: The model of vascular restenosis established by balloon injury of rabbit carotid common arteries was used. Immunohistochemistry, western blot and reverse transcriptase-polymerase chain reaction (RT - PCR) were used to detect the change of proliferation cell nuclear antigen ( PCNA ), smooth muscle α - actin ( SMα - actin ), P38 MAPK protein, and MKP-1 protein as well as its mRNA in vascular wall of sham-injured group and injury group at different time points.
Results: (1) Immunohistochemical staining of PCNA was negative in the medium and endothelium of sham-injured group. Positive cell percentage of PCNA was gradually increased at 1 ～14 days in the medium and at 5 ～14 days in the neointima after injury, and it reached peak value at 14 days. Positive cell percentage of PCNA was still higher though it was gradually declined after 28 days. Positive cell percentage of PCNA in the neointima was slightly more than that in the medium. (2) Immunohistochemical staining of SMα - actin was positive in the medium, negative in the endothelium of sham- injured artery. Positive expression area of SMα - actin in the medium initially decreased at 1 day and was minimal at 3 days after injury, but it increased gradually after 5 days, and was close to level of sham-injured artery at 28 days after injury. SMα -actin staining was always positive in the neointima at 5 ～35 days after injury, but its positive cells area was slightly less than that in the medium at different time points. (3) Immunohistochemical staining of P38 MAKP was negative or feeble positive in the medium of sham-injured artery. Positive expression area of P38 MAKP was significantly increased in the medium at 1 ～14 days and in the neointima at 5 ～14 days, and it was maximal at 14 days after injury. However, positive expression area of P38 MAKP initially decreased after 28 days, but its positive area was still significantly higher than that in sham-injured artery at 35 days after injury. P38 MAKP positive area in the neointima was higher than that in the medium. P38 MAKP examined by Western blot was sustained increased in vascular wall at 1～35 days after injury, in which it reached peak value at 14 days, initially decreased after 28 days. There were positive relationships between the change of P38 MAKP and PCNA in vascular wall at different time points after injury. (4) Immunohistochemical staining of MKP-1 was feeble positive or positive in the medium and endothelium of sham-injured artery. Its positive expression area in the medium progressing decreased at 1 ～3 days, and it reached lowest value at 5 ～ 7 days. At the same time, staining of MKP-1 was negative or feeble positive in the neointima. However, MKP-1 positive expression area was slightly increased from 14 to 28 days in the medium and the neointima. Its positive expression area was still lower than that sham-injured group at days 35 after injury. MKP-1 positive area in the neointima was slightly lower than that in the medium. The change of MKP-1 mRNA in vascular wall was consistent with immunohistochemical results. There were negative relationships between the change of MKP-1 and PCNA in the vascular wall at different time point after injury.
Conclusion: There was close relationship between phenotypic modulation and proliferating ability of VSMC. P38 MAPK and MKP-1 could participate in phenotypic modulation of VSMC and its regulation after intimal injury.
Part II
Experiment II
Effects of Tetrandrine on Phenotypic Modulation of Vascular Smooth Muscle Cells and Expression of P38 MAPK as well as MKP-1 after Intimal Injury of Rabbit Carotid Arteries
Objective: To study the effects of tetrandrine ( Tet ) on phenotypic modulation of vascular smooth muscle cells ( VSMC ) and P38 mitogen-activated protein kinase ( P38 MAPK) as well as mitogen - activated protein kinase phosphotase-1 ( MKP-1 ) after vascular intimal injury.
Methods: The model of vascular restenosis established by balloon intimal injury of rabbit carotid common arteries was used. HE staining was used to analysis vascular morphology change of sham-injured, injured and Tet-treated group at 28 days. Immunohistochemistry, Western blot and RT - PCR were respectively used to detect the expression change of proliferation cell nuclear antigen ( PCNA ), smooth muscle α-actin ( SMα-actin), P38 MAPK and MKP-1 of vascular wall in injured group and Tet group at 7, 14 and 28 days after injury. Results: (1) The each layer structure in vascular wall was intact in sham-injured group arteries at day 28. The neointimal area was significantly increased and the lumen area notably decreased in injured group at day 28. Compared with injured-group, the neointima proliferation degree was evidently decreased, and lumen area was markedly increased in Tet treated-group at day 28. (2) Compared with injured-group, the expression of PCNA, SMα-actin, P38 MAPK and MKP-1 in vascular wall of Tet group had no difference and the neointimal proliferation degree was also basically same at day 7 after injury. The expression of PCNA and P38 MAKP in Tet group was all obviously lower than that in injured-group, whereas the expression of MKP-1 in Tet group was evidently higher than that in injured-group in vascular wall at days 14 and 28 after injury, and all had time dependent manner. The expression of SMα-actin in Tet group was slightly higher than that in injured-group at days 14 and 28 after injury. Conclusions: Tet could reduce neointimal proliferation by inhibiting phenotypic modulation and P38 MAPK signal transduction pathway as well as its negative regulation of VSMC after intimal injury.
Part III
Expressional Change of MMP9, TIMP2 and Effects of Tet on Their Expression in Vascular Wall after Intimal Injury of Rabbit Carotid
Objective: To investigate (1) the effect of matrix metalloproteinases - 9 ( MMP9 ) and tissue inhibitors of metalloproteinases - 2 ( TIMP2 ) in extracellular matrix ( ECM ) formation of vascular restenosis; (2) the effects of tetrandrine (Tet) on MMP9, TIMP2 expression and vascular intimal proliferation. Methods: The model of restenosis established by balloon injury of rabbit carotid common arteries was performed. Immunohistochemistry, reverse transcriptase - polymerase chain reaction ( RT - PCR ) and Western blot were respectively used to detect the change of MMP9, TIMP2 mRNA and their protein expression in vascular wall as well as intimal proliferation in sham-injured group ( S group ) at 28 days, in injured group (I group ) and Tet-treated group ( Tet group ) at 7, 14 and 28 days after balloon injury. Results: (1) Positive expression area of MMP9 was higher in the medium at 7 days, and that it was gradually decreased at 14 and 28 days after injury; MMP9 positive expression area was lower relatively in the neointima at 7 days, and that it was significantly increased at 14 days, but it was obviously decreased at 28 days after injury. Positive expression area of TIMP2 in the medium and neointimal was lower at 7 days, and that it was significantly increased at 14 and 28 days after injury. (2) Compared with I group of same period, positive expression area of MMP9 and TIMP2 in the medium and neointimal of Tet group had no evident difference at 7 days, and that they were all respectively significantly decreased at 14 and 28 days after injury. At the same time, neointimal proliferation degree was also relieved and evidently relieved at 14 and 28 days after injury. (3) Expression of MMP9 mRNA and its protein was lower, and that the expression of TIMP2 mRNA and its protein was higher in vascular wall of S group. Compared with S group, expression of MMP9 mRNA and its protein in vascular wall of I group was stronger or higher at 7, 14, and 28 days. Expression of TIMP2 mRNA and its protein in vascular wall of I group was lower than that of S group at 7 days, and that it come back to or was higher than that of S group at 14 and 28 d. (4) Compared with I group of the same period, expression level of MMP9 mRNA and TIMP2 mRNA as well as their protein in vascular wall of Tet group had all no significant difference at 7 days, and that their expression of Tet group all had been significantly decreased at 14 days and 28 days after injury, in witch decrease of TIMP2 was more than that of MMP9. Conclusions: The lopsided increase and/or imbalance of MMP9 and TIMP2 expression played important role in ECM formation after vascular intimal injury. Tet could reduce abnormal higher expression of MMP9 and TIMP2 in vascular wall after intimal injury, ensure the equilibrium of MMP9 / TIMP2, and retard the accumulation and secretion of ECM, thereby inhibit neointimal hyperplasia and vascular remodeling.
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