血管内、外膜分别损伤诱发的动脉粥样硬化形成及MAPK/NF-κB信号通路的比较研究
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摘要
血管内皮损伤被一直认为是动脉粥样硬化(atherosclerosis,AS)发病的始动因素,而近年研究发现血管外膜参与了AS的形成,炎症、氧化应激可能是主要机制。无论是从内膜损伤还是从外膜损伤开始诱发的AS形成,炎症、氧化应激、免疫调节的失衡是共同的发病机制。炎症、氧化应激、免疫调节是通过各种信号通路传递信号的,内膜损伤和外膜损伤所引起的信号传递过程可能相似性,也可能有所不同。因此,我们拟通过在同一个体建立外膜损伤和经典的内膜损伤诱导AS形成的动物模型,比较两种病变形成共同和不同的规律、特点,比较“从内而外”和“从外而内”两种信号传递途径的异同,进一步了解外膜在AS发生、发展中的作用。全文由四部分组成。
第一部分内外膜损伤致动脉粥样硬化的模型的建立
目的:通过在同一个体建立外膜损伤和经典的内膜分别损伤诱导AS形成的动物模型,比较两种病变形成规律和特点的异同。
方法:在同一兔的两侧颈动脉,采用胶原酶分别消化颈动脉内皮和外膜的方法建立兔内膜和外膜损伤模型。分别于损伤后1w、2w、4w、8w取材,做石蜡切片和冰冻切片,采用HE、免疫组化、油红O染色方法,观察血管内膜增生情况及其构成成分。
结果:血管内、外膜损伤后1周即出现了内膜的增生,随着时间的延长,斑块面积进行性增大。1周时内膜损伤组IMR＜外膜损伤组(0.29±0.02 vs 0.11±0.01,p＜0.05),而1周后内膜损组内膜增生加速,逐渐与外膜损伤组相近,8w时内膜损伤组IMR＞外膜损伤组(0.63±0.05 vs 0.52±0.03)。油红O染色:可见血管损伤高脂饮食所致的病变中弥漫的橘红色阳性着色。α-actin免疫组化染色显示在血管损伤的早期血管病变内膜中有稀疏的阳性着色,提示病变中部分为平滑肌细胞。而随着病变的进展,无论是内膜损伤组还是外膜损伤组,血管内膜病变中CD68免疫组化染色有较密的阳性着色,提示病变中有大量巨噬细胞聚集。
结论:胶原酶消化法分别损伤血管内外膜,可有效破坏血管内外膜的完整性,诱发AS的形成。外膜损伤诱发的内膜增生早于内膜损伤,但AS程度轻于内膜损伤。
第二部分经血管外膜给药抑制MAPK及NF-κB信号通路的效果评价
目的:以Pluronic-F127(PF127)为载体,制作含有p38、JNK、NF-κB抑制剂的缓释凝胶,经血管外膜局部给药,观察对局部血管p38、JNK、NF-κB表达的抑制作用。
方法:制备PF127缓释凝胶,将p38、JNK、NF-κB抑制剂均匀溶解于PF127缓释凝胶,充填于血管周围。于给药后24h、72h、1w、2w、4w取材,用免疫组化和Western blot检测p38、JNK、NF-κB的表达情况。
结果:(1)p38抑制组:Western blot检测发现给药即刻、24h、72h p-p38的无明显变化(P＞0.05),1w开始,p-p38的表达明显下降(P＜0.05),与免疫组化结果相一致。而p38的表达在给药后的各个时间点均无明显变化。(2)JNK抑制组:给药后1w至4周,血管壁内、中、外膜的p-JNK表达均明显减少,至4w时完全看不到阳性颗粒。(2)NF-κB抑制剂组:免疫组化发现,外膜给药后1w内血管NF-κB p65的表达均无明显变化,而1w后至4w血管完全呈阴性(图2-5)。Western blot结果与免疫组化结果比较一致,蛋白表达量较低,0d～1w无显著差异(p＞0.05);1w后蛋白表达量明显降低(p＜0.05)
结论:经外膜给以PF127缓释凝胶为载体的p38、JNK、NF-κB抑制剂可有效抑制p38、JNK、NF-κB的表达。
第三部分MAPK、NF-κB信号通路在内外膜损伤诱导的AS形成中的作用
目的:比较MAPK、NF-κB通路在内外膜损伤诱导的AS形成过程中的变化规律;通过外膜给药的方法,特异性的抑制血管MAPK、NF-κB信号通路,明确MAPK—NF-κB信号通路在内外膜损伤致AS形成中的作用。
方法:在已建立的内外膜损伤模型的基础上,于模型建立后24h、72h、1w、2w、4w、8w取材,Western blot检测p38、JNK、ERK、NF-κB的表达的变化规律。经血管外膜给予含p38、JNK、NF-κB抑制剂的PF127缓释凝胶,观察2、4w血管内膜增生情况,以及p38、JNK、NF-κB的表达。
结果:血管内膜损伤和外膜损伤对MAPK和NF-κB的影响有相似点也不同之处。二者都可以引起p-p38、p-JNK和NF-κB表达的上调,但ERK则内外有别,外膜损伤不能上调ERK的表达,但内膜损伤则以上调ERK1为主。经外膜给含p-p38、p-JNK和NF-κB的缓释凝胶可有效抑制血管p-p38、p-JNK和NF-κB的表达,延缓AS进程。
结论:MAPK/NF-κB在内外膜损伤诱导的AS形成过程表达均明显增高,通过抑制MAPK/NF-κB信号通路可减轻损伤诱导的内膜增生。证明MAPK/NF-κBAS发生进展的重要通路。
第四部分通心络对内外膜损伤致AS形成的干预作用及机制
目的:观察通心络抑制血管内外膜损伤诱导的AS形成的效果,以及对MAPK、NF-κB信号通路的影响。
方法:在已建立的内外膜损伤模型的基础上,给予通心络干预8w。行HE、免疫组化和Western blot检查,观察通心络损伤诱导的内膜增生的抑制作用,以及对p38、JNK、ERK、NF-κB的表达影响。
结果:通心络可抑制内外膜损伤诱导的AS形成的作用,具有明显的抗动脉粥样硬化作用。通过对MAPK、NF-κB信号通路进行免疫组化和Western blot分析。通心络可以抑制内膜损伤组和外膜损伤组的p-p38、p-JNK的表达,而对于NF-κB,通心络仅能抑制内膜损伤组的表达,而对外膜损伤组则无作用。
结论:通心络可以抑制内膜和外膜损伤诱导的动脉粥样化的发生和进展,其机制可能与通心络抑制MAPK、NF-κB信号通路有关。
Endothelial injury has ever been regarded as the initiator of atherosclerosis.But recent research revealed that adventitia is not a bystander.What ever the adventitial and intimal injury induced atherosclerosis,Inflammation and oxidative stress and immune disorders might be the common mechanism.Inflammation,oxidative stress and immune conditioning messages pass through all kinds of pathway.Adventitia and endothelial injury induced signal transduction may transduct through the same pathway and different way.So we decided to establish a new model which exert adventitia injury and endothelial injury in two side carotid artery in one animal,which we can compare the different atherosclerosis at the same time.
PartⅠ:Establishment of the animal model of adventitia injury and endothelia injury induced atherosclerosis.
Object:The aim of this study was to establish rabbit model with carotid artery adventitial and intimal injury.
Method:The left carotid artery adventitia of rabbit was injured with collagenase digestion,meanwhile the contralateral one was injected with collagenase.Arteries were collected for paraffin sections and cryosection at 1、2、4、8 weeks after operation.Paraffin sections were stained with Hematoxylin and eosin to assess vascular morphology.Cryotomy sections were used for Oil Red O staining to identify fat deposits in the arteries.Immunohistochemical staining was performed to identify cellular components in intimal lesions.
Results:The results showed that intimal hyperplasia lesions occured 1 weeks after adventitial and endothelial injury in carotid arteries of rabbits.IMR(neointima area/media area×100%) of adventitia injurywithout adventitial injury were higher than endothelial injury side.(0.29±0.02 vs 0.11±0.01,p＜0.05).8 weeks later,the IMR of endothelial injury side surpass the adventitia injury side(0.63±0.05 vs 0.52±0.03).Rabbits fed with high fat diet developed classical atherosclerotic plaques were seen in both injured carotid arteries.As the experiment went on,the lesion represent a more lipid deposition and less smoothe muscle character.
PartⅡ:Evaluation of inhibitory effects on MAPK and NF-κB signal pathway by delivery through adventitia
Object:We prepared the p38、JNK and NF-κB inhibitor slow release delivery vehicle by Pluronic-F127(PF127),and delivered to the artery adventitia. Then we evaluate the effects of this system.
Methods:After PF127 gel was prepared,p38、JNK and NF-κB inhibitor were completely resolve in the gel.After we put the gel around the artery,24h、72h、1w、2w、4w later respectively,we collect the artery and examine the expression of p38、JNK、NF-κB by Immunochemistry and Western blot.
Results:(1) p38 inhibitor group:p-p38 expression didn't show significant after drug delivery of 24h to 72h.After 1 week,p-p38 expression reduced,which is consistant with Immunochemistry results.(2) JNK inhibitor group:1 to 4 weeks after delivery of JNK inhibitor,JNK expression obviously reduced in artery.After four weeks,there was no positive expression in artery.(3) NF-κB inhibitor group: Immunochemistry examination found that NF-κB p65 represents no difference in the artery.During 1 to 4 weeks,NF-κB p65 expression was negative in the artery. Western blot proved the same results,there was no difference in 1 week,but reduce during 1 to 4 weeks.
Conclusion:Delivery of p38、JNK、NF-κB inhibitor through adventitia may effectively inhibit the expression of p38、JNK、NF-κB.
PartⅢ:Role of MAPK、NF-κB in adventitia injury and endothelial induce atherosclerosis
Objects:After compared MAPK、NF-κB pathway in adventitia injury and endothelial induced atherosclerosis,we try to find out the role of MAPK、NF-κB in the pathogenesis of adventitia injury and endothelial injury induce atherosclerosis by adventitia delivery of specific MAPK、NF-κB inhibitor,
Methods:On the basis of animal in partⅠ,we examined p38、JNK、ERK、NF-κB expression by western blot after the animal model was established for 24h、72h、1w、2w、4w、8w.Then after deliverd of p38、JNK、NF-κB via adventitia,we examined the hyperplasia of intimal and the expression of p38、JNK、NF-κB.
Results:Both adventitia and endothelial can up regulate the expression of p38、JNK、NF-κB.Adventitia injury can't up regulate ERK,while endothelial can up regulation ERK1.Adventitia delivery of p-p38、p-JNK and NF-κB inhibitor can effectively inhibit the expression of p38、JNK、NF-κB and slow the progress of atherosclerosis.
PartⅣ:Effects and the mechanism of tongxinluo(TXL) on adventitial and endothelial injury induced atherosclerosis
Objectives:We hope to find the effects of TXL on adventitial and endothelial injury induced atherosclerosis,and suppression effects on APK、NF-κB signal pathoday.
Methods:On the basis of animal model established in partⅠ,TXL was administrator to the animals.After 8 weeks intervention,arteries were collected and examined by HE,immunochemistry and westem blot examination.The degree of intimal hyperplasia and expression of p38、JNK、ERK、NF-κB were examined.
Results:TXL may effectively inhibitor adventitia and endothelial injury induce AS, and present a anti-atherosclerosis character.By analysis of MAPK、NF-κB signal pathway via IHC and western blot,we found that TXL may inhibit the p-p38、p-JNK expression of both side,And TXL can just inhibit NF-κB expression in endothelial injury atherosclerosis.
第一部分内外膜损伤致动脉粥样硬化的模型的建立
目的:通过在同一个体建立外膜损伤和经典的内膜分别损伤诱导AS形成的动物模型,比较两种病变形成规律和特点的异同。
方法:在同一兔的两侧颈动脉,采用胶原酶分别消化颈动脉内皮和外膜的方法建立兔内膜和外膜损伤模型。分别于损伤后1w、2w、4w、8w取材,做石蜡切片和冰冻切片,采用HE、免疫组化、油红O染色方法,观察血管内膜增生情况及其构成成分。
结果:血管内、外膜损伤后1周即出现了内膜的增生,随着时间的延长,斑块面积进行性增大。1周时内膜损伤组IMR＜外膜损伤组(0.29±0.02 vs 0.11±0.01,p＜0.05),而1周后内膜损组内膜增生加速,逐渐与外膜损伤组相近,8w时内膜损伤组IMR＞外膜损伤组(0.63±0.05 vs 0.52±0.03)。油红O染色:可见血管损伤高脂饮食所致的病变中弥漫的橘红色阳性着色。α-actin免疫组化染色显示在血管损伤的早期血管病变内膜中有稀疏的阳性着色,提示病变中部分为平滑肌细胞。而随着病变的进展,无论是内膜损伤组还是外膜损伤组,血管内膜病变中CD68免疫组化染色有较密的阳性着色,提示病变中有大量巨噬细胞聚集。
结论:胶原酶消化法分别损伤血管内外膜,可有效破坏血管内外膜的完整性,诱发AS的形成。外膜损伤诱发的内膜增生早于内膜损伤,但AS程度轻于内膜损伤。
第二部分经血管外膜给药抑制MAPK及NF-κB信号通路的效果评价
目的:以Pluronic-F127(PF127)为载体,制作含有p38、JNK、NF-κB抑制剂的缓释凝胶,经血管外膜局部给药,观察对局部血管p38、JNK、NF-κB表达的抑制作用。
方法:制备PF127缓释凝胶,将p38、JNK、NF-κB抑制剂均匀溶解于PF127缓释凝胶,充填于血管周围。于给药后24h、72h、1w、2w、4w取材,用免疫组化和Western blot检测p38、JNK、NF-κB的表达情况。
结果:(1)p38抑制组:Western blot检测发现给药即刻、24h、72h p-p38的无明显变化(P＞0.05),1w开始,p-p38的表达明显下降(P＜0.05),与免疫组化结果相一致。而p38的表达在给药后的各个时间点均无明显变化。(2)JNK抑制组:给药后1w至4周,血管壁内、中、外膜的p-JNK表达均明显减少,至4w时完全看不到阳性颗粒。(2)NF-κB抑制剂组:免疫组化发现,外膜给药后1w内血管NF-κB p65的表达均无明显变化,而1w后至4w血管完全呈阴性(图2-5)。Western blot结果与免疫组化结果比较一致,蛋白表达量较低,0d～1w无显著差异(p＞0.05);1w后蛋白表达量明显降低(p＜0.05)
结论:经外膜给以PF127缓释凝胶为载体的p38、JNK、NF-κB抑制剂可有效抑制p38、JNK、NF-κB的表达。
第三部分MAPK、NF-κB信号通路在内外膜损伤诱导的AS形成中的作用
目的:比较MAPK、NF-κB通路在内外膜损伤诱导的AS形成过程中的变化规律;通过外膜给药的方法,特异性的抑制血管MAPK、NF-κB信号通路,明确MAPK—NF-κB信号通路在内外膜损伤致AS形成中的作用。
方法:在已建立的内外膜损伤模型的基础上,于模型建立后24h、72h、1w、2w、4w、8w取材,Western blot检测p38、JNK、ERK、NF-κB的表达的变化规律。经血管外膜给予含p38、JNK、NF-κB抑制剂的PF127缓释凝胶,观察2、4w血管内膜增生情况,以及p38、JNK、NF-κB的表达。
结果:血管内膜损伤和外膜损伤对MAPK和NF-κB的影响有相似点也不同之处。二者都可以引起p-p38、p-JNK和NF-κB表达的上调,但ERK则内外有别,外膜损伤不能上调ERK的表达,但内膜损伤则以上调ERK1为主。经外膜给含p-p38、p-JNK和NF-κB的缓释凝胶可有效抑制血管p-p38、p-JNK和NF-κB的表达,延缓AS进程。
结论:MAPK/NF-κB在内外膜损伤诱导的AS形成过程表达均明显增高,通过抑制MAPK/NF-κB信号通路可减轻损伤诱导的内膜增生。证明MAPK/NF-κBAS发生进展的重要通路。
第四部分通心络对内外膜损伤致AS形成的干预作用及机制
目的:观察通心络抑制血管内外膜损伤诱导的AS形成的效果,以及对MAPK、NF-κB信号通路的影响。
方法:在已建立的内外膜损伤模型的基础上,给予通心络干预8w。行HE、免疫组化和Western blot检查,观察通心络损伤诱导的内膜增生的抑制作用,以及对p38、JNK、ERK、NF-κB的表达影响。
结果:通心络可抑制内外膜损伤诱导的AS形成的作用,具有明显的抗动脉粥样硬化作用。通过对MAPK、NF-κB信号通路进行免疫组化和Western blot分析。通心络可以抑制内膜损伤组和外膜损伤组的p-p38、p-JNK的表达,而对于NF-κB,通心络仅能抑制内膜损伤组的表达,而对外膜损伤组则无作用。
结论:通心络可以抑制内膜和外膜损伤诱导的动脉粥样化的发生和进展,其机制可能与通心络抑制MAPK、NF-κB信号通路有关。
Endothelial injury has ever been regarded as the initiator of atherosclerosis.But recent research revealed that adventitia is not a bystander.What ever the adventitial and intimal injury induced atherosclerosis,Inflammation and oxidative stress and immune disorders might be the common mechanism.Inflammation,oxidative stress and immune conditioning messages pass through all kinds of pathway.Adventitia and endothelial injury induced signal transduction may transduct through the same pathway and different way.So we decided to establish a new model which exert adventitia injury and endothelial injury in two side carotid artery in one animal,which we can compare the different atherosclerosis at the same time.
PartⅠ:Establishment of the animal model of adventitia injury and endothelia injury induced atherosclerosis.
Object:The aim of this study was to establish rabbit model with carotid artery adventitial and intimal injury.
Method:The left carotid artery adventitia of rabbit was injured with collagenase digestion,meanwhile the contralateral one was injected with collagenase.Arteries were collected for paraffin sections and cryosection at 1、2、4、8 weeks after operation.Paraffin sections were stained with Hematoxylin and eosin to assess vascular morphology.Cryotomy sections were used for Oil Red O staining to identify fat deposits in the arteries.Immunohistochemical staining was performed to identify cellular components in intimal lesions.
Results:The results showed that intimal hyperplasia lesions occured 1 weeks after adventitial and endothelial injury in carotid arteries of rabbits.IMR(neointima area/media area×100%) of adventitia injurywithout adventitial injury were higher than endothelial injury side.(0.29±0.02 vs 0.11±0.01,p＜0.05).8 weeks later,the IMR of endothelial injury side surpass the adventitia injury side(0.63±0.05 vs 0.52±0.03).Rabbits fed with high fat diet developed classical atherosclerotic plaques were seen in both injured carotid arteries.As the experiment went on,the lesion represent a more lipid deposition and less smoothe muscle character.
PartⅡ:Evaluation of inhibitory effects on MAPK and NF-κB signal pathway by delivery through adventitia
Object:We prepared the p38、JNK and NF-κB inhibitor slow release delivery vehicle by Pluronic-F127(PF127),and delivered to the artery adventitia. Then we evaluate the effects of this system.
Methods:After PF127 gel was prepared,p38、JNK and NF-κB inhibitor were completely resolve in the gel.After we put the gel around the artery,24h、72h、1w、2w、4w later respectively,we collect the artery and examine the expression of p38、JNK、NF-κB by Immunochemistry and Western blot.
Results:(1) p38 inhibitor group:p-p38 expression didn't show significant after drug delivery of 24h to 72h.After 1 week,p-p38 expression reduced,which is consistant with Immunochemistry results.(2) JNK inhibitor group:1 to 4 weeks after delivery of JNK inhibitor,JNK expression obviously reduced in artery.After four weeks,there was no positive expression in artery.(3) NF-κB inhibitor group: Immunochemistry examination found that NF-κB p65 represents no difference in the artery.During 1 to 4 weeks,NF-κB p65 expression was negative in the artery. Western blot proved the same results,there was no difference in 1 week,but reduce during 1 to 4 weeks.
Conclusion:Delivery of p38、JNK、NF-κB inhibitor through adventitia may effectively inhibit the expression of p38、JNK、NF-κB.
PartⅢ:Role of MAPK、NF-κB in adventitia injury and endothelial induce atherosclerosis
Objects:After compared MAPK、NF-κB pathway in adventitia injury and endothelial induced atherosclerosis,we try to find out the role of MAPK、NF-κB in the pathogenesis of adventitia injury and endothelial injury induce atherosclerosis by adventitia delivery of specific MAPK、NF-κB inhibitor,
Methods:On the basis of animal in partⅠ,we examined p38、JNK、ERK、NF-κB expression by western blot after the animal model was established for 24h、72h、1w、2w、4w、8w.Then after deliverd of p38、JNK、NF-κB via adventitia,we examined the hyperplasia of intimal and the expression of p38、JNK、NF-κB.
Results:Both adventitia and endothelial can up regulate the expression of p38、JNK、NF-κB.Adventitia injury can't up regulate ERK,while endothelial can up regulation ERK1.Adventitia delivery of p-p38、p-JNK and NF-κB inhibitor can effectively inhibit the expression of p38、JNK、NF-κB and slow the progress of atherosclerosis.
PartⅣ:Effects and the mechanism of tongxinluo(TXL) on adventitial and endothelial injury induced atherosclerosis
Objectives:We hope to find the effects of TXL on adventitial and endothelial injury induced atherosclerosis,and suppression effects on APK、NF-κB signal pathoday.
Methods:On the basis of animal model established in partⅠ,TXL was administrator to the animals.After 8 weeks intervention,arteries were collected and examined by HE,immunochemistry and westem blot examination.The degree of intimal hyperplasia and expression of p38、JNK、ERK、NF-κB were examined.
Results:TXL may effectively inhibitor adventitia and endothelial injury induce AS, and present a anti-atherosclerosis character.By analysis of MAPK、NF-κB signal pathway via IHC and western blot,we found that TXL may inhibit the p-p38、p-JNK expression of both side,And TXL can just inhibit NF-κB expression in endothelial injury atherosclerosis.
引文
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3.Shi Y,Niculescu R,Wang D,et al.Increased NAD(P) H oxidase and reactive oxygen species in coronary arteries after balloon injury[J].Arterioscler Thromb Vasc Biol,2001,21:73927451.
4.Siow RC,Mallawaarachchi CM,Weissberg PL et al.Migration of adventitial myofibroblast s following vascular balloon injury:insight s from in vivo gene transfer to rat carotid arteries[J].Cardiovasc Res,2003,59:21222211.
5.Allbutt C.Diseases of the artries including angina pectoris[M].London:Macmillan Co,1915;468.
6.Schwartz CJ,Mitchell JRA.Cellular infiltration of the human arterial adventitia associated with atheromatous piques[J].Circulation,1962,26:73278.
7. Higuchi ML , Gutierrez PS , Bezerra HG, et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries [J]. Arq Bras Cardiol, 2002, 79: 20224.
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10. Hu Y, Zhang Z , Torsney E , et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein graf t s in apo E deficient mice[J].J Clin Invest,2004,113:1258212651.
11. Barker SGE, Tilling LC, Miller GC et al. The adventitia and atherogenesis: removal initiates intimal proliferation in the rabbit which regresses on generation of a'neoadventitia' [J]. Atherosclerosis, 1994;105:131-144.
12. Rayner K, Ersel SV, Groot PH, et al.Localization of mRNA for JE/MCP-1 and its receptor CCR2 in atherosclerotic lesions of ApoE knockout mouse[J] J Vasc Res,2000,37:93-102.
13. Wilcox JN, Scott NA. Potential role of the adventitia in arteritis and atherosclerosis[J]. Int J Cardiol, 1996,54(suppl):S21-S35.
14. Moreno PR, Purushothaman KR, Fuster VO, et al. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implication for plaque vulnerability [J]. Circulation, 2002,105:2504-511.
15. Maria L. Higuchi, Paulo S. Gutierrez, Hiram G. Bezerra, et al. Comparison between Adventitial and Intimal Inflammation of Ruptured and Nonruptured Atherosclerotic Plaques in Human Coronary Arteries[J]. Arq. Bras. Cardiol. vol.79 no.1 Sao Paulo July 2002.
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2.Yun A J,Doux JD,Bazar KA,Lee PY.Adventitial dysfunction:an evolutionary model for understanding atherosclerosis.Med Hypotheses.2005;65(5):962-5.
3. Moreno PR, Purushothaman KR, Fuster V, O'Connor WN. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implications for plaque vulnerability. Circulation. May 28 2002;105(21):2504-11.
4. Higuchi ML, Gutierrez PS, Bezerra HG et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries. Arq Bras Cardiol. Jul 2002;79(1):20-4.
5. Prescott MF, McBride CK, Court M. Development of intimal lesions after leukocyte migration into the vascular wall. Am J Pathol. Nov 1989;135(5):835-46.
6. Moos MP, John N, Grabner R et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. Nov 2005;25(11):2386-91.
7. Li G, Chen SJ, Oparil S et al. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation. Mar 28 2000;101(12):1362-5.
8. Dourron HM, Jacobson GM, Park JL et al. Perivascular gene transfer of NADPH Oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery. Am J Physiol Heart Circ Physiol. Feb 2005;288(2):H946-53.
9. Jacobson GM, Dourron HM, Liu J et al. Novel NAD(P)H Oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery. Circ Res. Apr 4 2003;92(6):637-43.
10. Chi H, Barry SP, Roth RJ et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK Phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci USA. Feb 14 2006;103(7):2274-9.
11. Pyles JM, March KL, Franklin M et al. Activation of MAP kinase in vivo follows balloon overstretch injury of porcine coronary and carotid arteries. Circ Res.Dec 1997;81(6):904-10.
12. Madonna R, Massaro M, Pandolfi A et al. The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells. Int J Immunopathol Pharmacol. Jul-Sep 2007;20(3):539-55.
13. Hedges JC, Dechert MA, Yamboliev IA et al. A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J Biol Chem. Aug 20 1999;274(34):24211-9.
14. Garcia-Trapero J, Carceller F, Dujovny M, Cuevas P. Perivascular delivery of neomycin inhibits the activation of NF-kappaB and MAPK pathways, and prevents neointimal hyperplasia and stenosis after arterial injury. Neurol Res. Dec 2004;26(8):816-24.
15. Barker SG, Tilling LC, Miller GC et al. The adventitia and atherogenesis: removal initiates intimal proliferation in the rabbit which regresses on generation of a 'neoadventitia'. Atherosclerosis. Feb 1994;105(2):131-44.
1.Sartore S,Chiavegato A,Faggin E,et all Contribution of adventitialfibroblasts to neointima formation and vascular remodeling:from innocent bystander to active participant[J].Circ Res,2001,89:1111211211.
2.Dzau VJ,Braun2Dullaeus RC,Sedding DG.Vascular proliferation and atherosclerosis:new perspectives and therapeutic st rategies[J].Nat Med,2002,8:1249212561.
3.Shi Y,Niculescu R,Wang D,et al.Increased NAD(P) H oxidase and reactive oxygen species in coronary arteries after balloon injury[J].Arterioscler Thromb Vasc Biol,2001,21:73927451.
4.Siow RC,Mallawaarachchi CM,Weissberg PL et al.Migration of adventitial myofibroblast s following vascular balloon injury:insight s from in vivo gene transfer to rat carotid arteries[J].Cardiovasc Res,2003,59:21222211.
5.Allbutt C.Diseases of the artries including angina pectoris[M].London:Macmillan Co,1915;468.
6.Schwartz CJ,Mitchell JRA.Cellular infiltration of the human arterial adventitia associated with atheromatous piques[J].Circulation,1962,26:73278.
7. Higuchi ML , Gutierrez PS , Bezerra HG, et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries [J]. Arq Bras Cardiol, 2002, 79: 20224.
8. Rayner K, Van Eersel S , Groot PH, et al. Localisation of mRNA for JEPMCP21 and its receptor CCR2 in atherosclerotic lesions of the Apo E knockout mouse[J]. J Vasc Res, 2000, 37: 932102.
9. Saiura A, Sata M, Hirata Y, et al.Circulating smooth muscle progenitor cells cont ribute to atherosclerosis[J].Nat Med, 2001,7 :38223831.
10. Hu Y, Zhang Z , Torsney E , et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein graf t s in apo E deficient mice[J].J Clin Invest,2004,113:1258212651.
11. Barker SGE, Tilling LC, Miller GC et al. The adventitia and atherogenesis: removal initiates intimal proliferation in the rabbit which regresses on generation of a'neoadventitia' [J]. Atherosclerosis, 1994;105:131-144.
12. Rayner K, Ersel SV, Groot PH, et al.Localization of mRNA for JE/MCP-1 and its receptor CCR2 in atherosclerotic lesions of ApoE knockout mouse[J] J Vasc Res,2000,37:93-102.
13. Wilcox JN, Scott NA. Potential role of the adventitia in arteritis and atherosclerosis[J]. Int J Cardiol, 1996,54(suppl):S21-S35.
14. Moreno PR, Purushothaman KR, Fuster VO, et al. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implication for plaque vulnerability [J]. Circulation, 2002,105:2504-511.
15. Maria L. Higuchi, Paulo S. Gutierrez, Hiram G. Bezerra, et al. Comparison between Adventitial and Intimal Inflammation of Ruptured and Nonruptured Atherosclerotic Plaques in Human Coronary Arteries[J]. Arq. Bras. Cardiol. vol.79 no.1 Sao Paulo July 2002.
16．牟华明,祝之明,王海燕,等．兔血管外膜对血管重构及收缩功能影响的初步观察[J]．生理学报,June 25,2003,55：290-295．
1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. Jan 14 1999;340(2): 115-26.
2. Huehns TY, Gonschior P, Hofling B. Adventitia as a target for intravascular local drug delivery. Heart. Jun 1996;75(6):537-8.
3. Liu J, Ormsby A, Oja-Tebbe N, Pagano PJ. Gene transfer of NAD(P)H Oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ Res. Sep 17 2004;95(6):587-94.
4. Escobar-Chavez JJ, Lopez-Cervantes M, Naik A et al. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J Pharm Pharm Sci. 2006;9(3):339-58.
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