摘要
1.背景与目的:
迄今靶病变血管再狭窄(RS)仍然是经皮冠状动脉介入(PCI)术后最主要的问题之一。Forrester等提出,支架内RS的主要原因是血管内膜损伤后,自身愈合过程导致的新生内膜增生,是血管内皮修复和内膜增殖的对立平衡失调的结果。当前对于RS的防治主要集中在药物、基因治疗、介入治疗以及外科手术等方面,虽然这些治疗手段从一定程度上减轻了RS所造成的危害,但对于血管损伤处的内皮修复和抑制内膜增生的作用仍难以令人满意。如何寻找一种更佳的方法促进血管损伤后再内皮化和抑制过度的新生内膜增殖,从而达到预防和治疗RS的目的是当今的研究热点。
众多的研究相继证实内源性电场广泛存在于损伤愈合、组织再生、胚胎发育以及肿瘤的形成等生理或病理生理过程。在机体自身产生的生物电场不足以促进损伤愈合的过程时,在损伤区与非损伤区之间施加直流电场可以增强损伤愈合速率。内皮损伤在增殖性血管疾病发病中起始动和促进作用,平滑肌细胞(VSMCs)的增殖和迁移是构成血管新生内膜增生的直接原因。有研究发现,生理强度直流电场对血管内皮细胞的多种生物学行为产生影响。外加电场还可以诱导血管内皮细胞肌动蛋白细胞骨架F-actin合成和装配,进而影响细胞运动行为。研究表明外加电场可以影响VSMCs的定向迁移,这种作用是与细胞生长相关的一种主动行为,而不是在电场作用下的一种被动的泳动。离体实验发现外加电场也可以影响VSMCs的增殖。内源性电场也存在于血管周围,在体情况下,适宜的外加电场可以改善电场作用局部的动脉粥样硬化程度。因此,在体情况下外加低压稳恒直流电场是否会影响血管周围的内源性电场,是否会影响血管损伤后的修复过程值得探讨。
本课题小组已在前期研究中初步探讨了稳恒直流电场对培养VSMCs的作用及机制,并设计了电场作用于实验动物的电源装置。在此基础上,本课题进一步将稳恒直流电场作用于血管损伤动物模型,研究其对血管损伤后新生内膜增生以及血管再内皮化的影响及其机制。
2.方法:
第一部分初步探讨外加低压稳恒直流电场作用于血管时的可行性及安全有效的方式。
(1)将自制的铂电极置于家兔腹主动脉两侧腰大肌内,或将铂电极分别置于腹主动脉血管内和家兔颈背部,观察不同电场作用方式、不同电场强度下血管局部损伤情况的变化。
(2)将两自制铂电极置于家兔腹主动脉两侧腰大肌内作为刺激电极,通过多对测量电极观察不同电压强度下兔腹主动脉周围电势差的变化情况。
第二部分将健康日本大耳白兔65只,随机分为假手术组、对照组、实验组,其中实验组分为3.0V、4.0V两个亚组。建立兔腹主动脉球囊损伤模型,将自制的铂电极置于家兔腹主动脉两侧腰大肌内,根据分组情况给与实验组相应的稳恒直流电场刺激,于术后1周,术后2周,术后4周处死动物。通过伊文氏蓝染色、CD31免疫组化、扫描电镜来观察血管再内皮化情况;观察各组离体血管环对不同浓度乙酰胆碱的最大舒张反应,判断血管内皮依赖性舒张功能;通过HE染色,天狼猩红染色以及Western-blot来观察血管新生内膜增生情况和Ⅰ型、Ⅲ型胶原蛋白的表达。
第三部分通过PCNA免疫组化和TUNEL法观察外加稳恒直流电场刺激后血管平滑肌细胞增殖和凋亡情况变化,通过免疫组化、Western-blot和实时定量PCR来观察电场刺激后P27和PTEN的表达变化。
3.结果
(1)将铂丝电极置入血管内,连接血管外电极和电源可构成透壁电场。此干预方式使用1.0V电压刺激即可灼伤血管内膜。由于电极置入血管内,极易引起血栓的形成。
(2)将铂电极置入兔腹主动脉两侧腰大肌,连接电源后构成平面电场,此干预方式比较安全。通电后即刻血管外膜间和血管内外膜间的电势差不会马上发生改变;通电后30分钟,3.0V和4.0V组血管外膜间和血管内外膜间的电势差与通电前相比均显著升高(P<0.01);断开电源30分钟后,3.0V和4.0V组血管内外膜间的电势差仍高于通电前(P<0.01),两刺激电极间仍能保持较高的电势差。
(3)伊文氏蓝染色结果显示3.0V组和4.0V组各时间点内皮再生面积/损伤总面积比值与对照组相比均无显著差异(P>0.05)。4.0V电场干预4周后血管环对Ach的最大舒张反应高于对照组和3.0V组(P<0.05),其余时间点血管环对Ach的最大舒张反应与对照组和3.0V组比较均无显著差异。
(4)在球囊损伤后2周和4周,3.0V组和4.0V组内/中膜面积比值均显著小于对照组,3.0V组和4.0V组之间比较无显著差异(P>0.05)。天狼猩红染色显示3.0V组和4.0V组血管新生内膜中Ⅰ型、Ⅲ型胶原蛋白的表达低于对照组。
(5)在兔腹主动脉球囊损伤模型,血管内膜损伤后血管壁的细胞凋亡水平较低,3.0V或4.0V外加稳恒直流电场干预后细胞凋亡未见增加;
(6)在球囊损伤后2周,3.0V组和4.0V组PCNA阳性增殖细胞指数均显著小于对照组(P<0.01),球囊损伤后4周电场干预组与对照组相比增殖细胞指数间均无显著差异(P>0.05);
(7) 3.0V和4.0V外加稳恒直流电场均可以上调血管损伤后P27的表达;
(9)血管球囊损伤后,PTEN的表达下降,给予3.0V或4.0V外加稳恒直流电场干预后,血管壁内PTEN蛋白的表达上调。
4.结论
(1)外加稳恒直流电场干预不会影响血管损伤后的再内皮化速度,4.0V电场干预4周后血管内皮依赖性舒张功能较对照组和3.0V组有改善,提示适宜的外加电场可能有利于内皮功能的恢复。
(2)适宜的外加稳恒直流电场可以抑制血管损伤后新生内膜的增生,同时也抑制了新生内膜内Ⅰ型、Ⅲ型胶原蛋白的表达。
(3)外加稳恒直流电场抑制新生内膜的增生可能是通过影响VSMCs增殖来实现的,而不是通过促进细胞的凋亡。
(4)外加3.0V和4.0V稳恒直流电场均可以上调血管损伤后血管壁内P27和PTEN的表达,提示在体情况下,外加电场抑制新生内膜增生的机制可能是通过PTEN-P27途径而发挥作用的。
1. Background and Objective:
Vascular restenosis is still one of the major problems after percutaneous coronary intervention (PCI). Forrester suggested that the main reason responsible for in-stent restenosis was the hyperplasia of new intima resulted from the process of self-healing after injury of vascular endothelium, and was the result of the contrary balance between endothelial repair and intimal hyperplasia. At present, the prevention of restenosis mainly focuses on the aspects including drug therapy, gene therapy, interventional therapy and surgery. Although these measures alleviate harms caused by restenosis to some extent, their effects on the endothelial recovery and the inhibition of intimal hyperplasia at the injury sites of vessels are still not satisfying. Therefore, it is the hotspot of present researches how to find out a better method to promote reendothelialization after vessel injury and inhibit excessive neointimal hyperplasia, so as to achieve the prevention and treatment purposes of restenosis.
It has been approved that the endogenous electrical field widely exists in the physiological or pathophysiological processes, such as injury healing, tissue regeneration, embryonic development and tumor formation. The injury healing rate can be enhanced by applying direct current electrical fields between the injury zone and the non-injury zone when the bioelectrical field generated by the body itself is not enough to induce the injury to heal. Endothelial injury plays the start-up and promotion role in the pathogenesy process of proliferative vessel diseases, and the proliferation and migration of vascular smooth muscle cells(VSMCs) are the immediate reason responsible for intimal hyperplasia of vessels. Some researches indicated that direct current electrical fields with physiological intensity could influence a plurality of biological behaviors of vascular endothelial cells. The applied electrical fields could also induce the synthesis and assembly of F-actin in vascular endothelial cells, and further affect their motion behaviors. Researches suggested that the directional migration of VSMCs could be affected by the applied electrical fields, which was an initiative activity related to the cell growth rather than a passive swimming motility under the influence of electrical fields. Experiments in vitro revealed that the proliferation of VSMCs could also be affected by the applied electrical fields. The endogenous electrical field existed around the vessels as well, and suitable applied electrical fields could improve the extent of local atherosclerosis around the electrical field in vivo. Therefore, it was worthy of investigating whether the endogenous electrical field around vessels and the repair process after vessel injury could be influenced by the applied steady direct current electrical fields.
The effects and mechanism of the applied weak steady direct current electrical fields on VSMCs were preliminarily studied by our research group, and a power device used for applying the electrical fields to experimental animals was designed. Based on the researches mentioned above, the steady direct current electrical fields were further applied to the animals with injured vessel in this thesis to investigate its roles and mechanisms on neointimal hyperplasia and vascular reendothelialization after vessel injury.
2. Methods
(1) In section 1, the feasibility of applying steady direct current electrical fields to vessels as well as its safety and efficiency were investigated.
①Two self-made platinum electrodes were placed in the psoas major muscles at both sides of the abdominal aorta of rabbit, or in the lumens of the abdominal aorta and nape part of the rabbit, respectively. Then, the local injury of the vessel was observed under the condition of the plane electrical field or the transmural electrical field.
②Two self-made platinum electrodes used as the stimulating electrode were placed in the psoas muscles at both sides of the abdominal aorta of rabbit, and variations of the potential difference around the abdominal aorta of rabbit under different voltage intensities were observed using several couples of measuring electrodes.
(2) In section 2, the model of balloon injury abdominal aorta of rabbit was established. 65 healthy Japanese white rabbits were randomly divided into sham group, control group and experiment group. And the experiment group was further divided into 3.0V group and 4.0V group, in which corresponding interventions of direct current electrical fields were applied to the rabbits. The rabbits were sacrificed on 1st, 2nd, 4th week. Vascular reendothelialization was observed using evans blue staining, CD31 immunohistochemistry and SEM; while neointimal hyperplasia and extracellular matrix were observed through HE staining, sirius red staining and western-blot.
(3) In section 3,cell proliferation and apoptosis were observed using the methods of PCNA immunohistochemistry and TUNEL,while variations of P27 and PTEN were observed through immunohistochemistry, western-blot and quantitative real-time PCR.
3. Results
(1) After the platinum wire electrode was implanted in the lumens of vessel, it connected with the electrode and power supply outside the vessel, then constituted the transmural electric field. With the stimulation of just 1.0V voltage, the vascular intima could be burned by this kind of intervention. As the electrode was placed in the lumens of vessel, the formation of thrombosis could be easily produced.
(2) The platinum wire electrode was placed in the psoas major muscle in the two sides of abdominal aorta of rabbit, and with the connection of the power supply, the electric field in the plane was formed. This kind of intervention method was safe relatively. The electric potential difference between exterior and interior vascular tunic didn’t have changes immediately after the power supply was connected. After the connection with the power supply for 30min, the electric potential difference between exterior and interior vascular tunic both in the 3.0V and 4.0V groups increased significantly compared with that of pre-therapy (P <0.01). When there was no electric supply for 30min, the electric potential difference between exterior and interior vascular tunic both in the 3.0V and 4.0V group was still higher than that with no electric supply(P <0.01), and the high electric potential difference could be found between the two stimulating electrodes as well.
(3) The result of Evans blue staining indicated that the ratio between the area with endothelium regeneration and the total injured area in the 3.0V and 4.0V groups had no significant difference compared with that of the control group (P> 0.05) on all time points. After 4 weeks of electric field intervention, the largest vasorelaxation reactivity of vascular ring towards Ach of 4.0V group was greater than that of the control group and 3.0V group (P <0.05). But there were no significant difference among all these groups on other time point.
(4) After 2 weeks and 4 weeks of the balloon injury, the ratio between the vascular intima and tunica media in the 3.0V and 4.0V groups was smaller than that of control group, and it had no significant difference between the 3.0V and 4.0V groups (P>0.05). The Sirius red staining showed that the expression of type-I and type-Ⅲcollagen protein in the vascular neointimal was lower than that of the 3.0V and 4.0V groups.
(5) In the model of abdominal aorta balloon injury of rabbit, the level of cell apoptosis of vascular wall after the vascular intimal injury was relatively low and was not strengthened under the intervention of steady direct current electric fields of 3.0V or 4.0V.
(6) After 2 weeks of balloon injury, the PCNA positive proliferation cell index in both the 3.0V and 4.0V groups was lower than that of the control group (P<0.01), but no significant difference was found after 4 weeks of balloon injury(P>0.05).
(7) The steady direct current electric fields of 3.0V and 4.0V could up-regulate the expression of P27 after the vascular injury.
(8) After vascular balloon injury, the PTEN expression declined, and with the intervention of steady direct current electric fields of 3.0V and 4.0V, the expression of PTEN protein in the vascular wall was up-regulated.
4. Conclusions
(1) The reendothelialization rate after vessel injury could not be influenced by the intervention of a applied steady direct electrical field, and the diastolic function of the vascular endothelium depending was improved by the intervention of 4.0V electrical field for 4 weeks compared to those in 3.0V group, indicating a suitable applied electrical field was favorable for the recovery of endothelial functions.
(2) Neointimal hyperplasia after vessel injury, as well as the expression of proteins in the of type I and type III collagen of the neointima could be inhibited by a suitable applied steady direct current electrical field.
(3) Inhibition of the neointimal hyperplasia by the applied steady direct current electrical field might be accomplished by influencing the proliferation of smooth muscle cells rather than promoting apoptosis. The expression of P27 and PTEN in the vessel wall after vessel injury could be enhanced by both applied steady direct current electrical fields with voltages of 3.0V and 4.0V, indicating inhibition of new intimal hyperplasia by the applied steady direct current electrical field might take effects through PTEN-P27 pathway in vivo.
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