Name: a rabbit venous interposition model mimicking revascularization surgery using vein grafts to assess intimal hyperplasia under arterial blood pressure
Uploaded: 2020-05-15T13:30:00
Description: Watch this Scientific Journal Video about A Rabbit Venous Interposition Model Mimicking Revascularization Surgery using Vein Grafts to Assess Intimal Hyperplasia under Arterial Blood Pressure at JoVE.

这项工作得到了日本教育、文化、体育、科学和技术部的研究资助（25462136） 的支持。

注：所有对动物进行的外科手术均应按照《实验室动物护理和使用指南》（www.nap.edu/catalog/5140.html）或其他适当的道德准则进行。议定书应在继续之前得到有关机构动物福利委员会的批准。
1. 动物的准备
<ol><li>购买体重2.7~3.0公斤的雄性日本白兔（或体型相当的兔子）。</li>
	<li>在12小时的光暗周期中使兔子适应1周，并在手术前定期喂兔子周食。</li>
</ol>2. 麻?...

<ol>
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E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+production+of+aneurysms+by+microvascular+surgery+in+rabbits.">Experimental production of aneurysms by microvascular surgery in rabbits.</a> Vascular Surgery. 7 (3), 165-175 (1973).</li><li>Bannister, C. M., Mundy, L. A., Mundy, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fate+of+small+diameter+cervical+veins+grafted+into+the+common+carotid+arteries+of+growing+rabbits.">Fate of small diameter cervical veins grafted into the common carotid arteries of growing rabbits.</a> Journal of Neurosurgery. 46 (1), 72-77 (1977).</li><li>Bergmann, M., Walther, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ultrastructural+changes+of+venous+autologous+bypass+grafts+in+rabbits:+correlation+of+patency+and+development.">Ultrastructural changes of venous autologous bypass grafts in rabbits: correlation of patency and development.</a> Basic Research in Cardiology. 77 (6), 682-694 (1982).</li><li>Murday, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intimal+hyperplasia+in+arterial+autogenous+vein+grafts:+a+new+animal+model.">Intimal hyperplasia in arterial autogenous vein grafts: a new animal model.</a> Cardiovascular Research. 17 (8), 446-451 (1983).</li><li>Quist, W. C., LoGerfo, F. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevention+of+smooth+muscle+cell+phenotypic+modulation+in+vein+grafts:+a+histomorphometric.">Prevention of smooth muscle cell phenotypic modulation in vein grafts: a histomorphometric.</a> Journal of Vascular Surgery. 16 (2), 225-231 (1992).</li><li>Davies, M. G., Dalen, H., Svendsen, E., Hagan, P. 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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgical+vein+graft+preparation+promotes+cellular+dysfunction,+oxydative+stress,+and+intimal+hyperplasia+in+human+saphenous+vein.">Surgical vein graft preparation promotes cellular dysfunction, oxydative stress, and intimal hyperplasia in human saphenous vein.</a> Journal of Vascular Surgery. 60 (1), 202-211 (2014).</li><li>Shintani, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intraoperative+transfection+of+vein+grafts+with+the+NFkappaB+decoy+in+a+canine+aortocoronary+bypass+model:+a+strategy+to+attenuate+intimal+hyperplasia.">Intraoperative transfection of vein grafts with the NFkappaB decoy in a canine aortocoronary bypass model: a strategy to attenuate intimal hyperplasia.</a> Annals of Thoracic Surgery. 74 (4), 1132-1137 (2002).</li><li>Petrofski, J. 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本协议旨在提供一个实验平台，用于测试 VSMC 的各种分子或基因干预，以控制表型从增殖状态到收缩状态，进而衰减体内静脉内刺激增生的进展。利用这个模型，我们在手术后2周成功地制备了内皮增生（图1A），并指明了微RNA-145控制VSMC表型26、27,27的治疗潜力，验证了本发明作为模型，以进一步研究静脉增生的衰减。
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全世界因动脉粥样硬化而患缺血性疾病的患者数量正在增加1。尽管目前心血管疾病的医学和外科治疗取得了进步，但缺血性心脏病，如心肌梗死，仍然是导致发病率和死亡率的主要原因2。此外，以四肢血流量减少为特征的外周动脉疾病诱发严重的肢体缺血，其中约40%的患者在诊断后6个月内失去双腿，死亡率高达20%3。
再血管化手术，如冠状动脉旁路移植（CABG）和周围动脉旁路手术，是缺血性疾病的主要治疗选择。这些手术的目的是提供一个新的血液途径，提供足够的血液流向动脉的硬骨或阻塞病变的远端部位。虽然原位动脉移植，如CABG的内部胸动脉，是首选作为旁路移植，因为预期的更长的光度，静脉移植，如自体性沙芬静脉，是常用的，因为更高的可及性和可用性4。静脉移植的薄弱环节是动脉移植率比动脉移植率低，在动脉压力下加速增生，导致静脉移植病6。
静脉移植疾病通过以下三个步骤发展：1） 血栓;2） 暗示性增生;和3）动脉粥样硬化7。为了解决静脉移植病，已经进行了大量的基础研究。到目前为止，除了抗血小板和降脂疗法外，没有建议,在近期指南9、10、11、1210中进行冠状动脉或外周9再血管化手术后进行二次预防。11,12因此，为了克服静脉移植疾病，特别是静脉增生，需要建立相关的实验平台，供进一步研究。
肌增多是一种适应现象，发生在对周围环境变化的反应中，血管平滑肌肉细胞 （VSMC） 在肌阵中增殖、积累和生成细胞外基质。因此，它为移植异质7提供了基础。在超塑性内皮中，VSMC承担增殖，生产而不是收缩，称为"象形变化"8。控制静脉移植的VSMC表型，预防静脉移植疾病，是一项关键的研究目标，并为此课题8进行了许多基础研究。然而，一项旨在实现VSMC表型药理控制的随机对照临床研究显示，结果有限。此外，没有标准化的疗法来防止内量增生。更多的基础研究，包括动物模型研究，是必要的。
为了促进这一领域的研究，建立一个动物模型，在动脉血压下重述静脉移植，允许长期的术后观察是至关重要的。Carrel等人建立了将外管静脉植入胡萝卜动脉14的一种狗模型。之后，各种静脉移植物被用于调查动脉血压变化的生理和病理影响，包括下部静脉卡巴移植到胸腔或腹部主动脉，或移植到股动脉15、16、1716,17的沙赫诺静脉。15这些模型建在较大的动物，如猪或狗，适合模仿静脉移植疾病在临床的情况下。然而，建立一个动物模型，可以准备没有特殊的手术技术，以较低的成本将是研究人员试图开发新的治疗策略，通过VSMC表型控制在体内衰减体内的增生。最初，在神经外科18、19,19领域，将血管插入兔子的胡萝卜动脉。此后，它应用于20、21,21年恶性增生研究。初始模型仅由静脉互置组成，从而节省时间。此外，随后的研究表明，静脉移植的制备也影响了静脉增生22。Davies等人评估了气球导管损伤对兔子静脉介词模型23、24,24中刺激性增生的影响。虽然气球导管损伤，除了静脉介词更相关的临床设置，一个更可重现的模型也要求。因此，江等人考察了差流量环境对突增增生的影响，建立了远端分支结扎程序，作为可重现的模型25。然而，他们在静脉移植介位时采用了袖口技术，在临床环境中似乎不同于手工缝合的麻醉。在本协议中，我们报告一个可重复的，临床相关，和广泛的程序，准备兔子静脉介词模型，以评估动脉血压下的内量增生。

<table>
	<tbody>
		<tr>
			<td>10% Povidone-iodine solution</td>
			<td>Nakakita</td>
			<td>872612</td>
			<td>Surgical expendables</td>
		</tr>
		<tr>
			<td>2-0 VICRYL Plus</td>
			<td>Johnson and Johnson</td>
			<td>VCP316H</td>
			<td>Surgical expendables</td>
		</tr>
		<tr>
			<td>4-0 Silk suture</td>
			<td>Alfresa pharma</td>
			<td>GA04SB</td>
			<td>Surgical expendables</td>
		</tr>
		<tr>
			<td>8-0 polypropylene suture</td>
			<td>Ethicon</td>
			<td>8741H</td>
			<td>Surgical expendables</td>
		</tr>
		<tr>
			<td>Cefazorin sodium</td>
			<td>Nichi-Iko Pharmaceutical</td>
			<td>6132401D3196</td>
			<td>Antibiotics</td>
		</tr>
		<tr>
			<td>Fogarty Catheter (2Fr)</td>
			<td>Edwards Lifesciences LLC</td>
			<td>E-060-2F</td>
			<td>Surgical expendables</td>
		</tr>
		<tr>
			<td>Heparin</td>
			<td>Nipro</td>
			<td>873334</td>
			<td>Anticoagulant</td>
		</tr>
		<tr>
			<td>Intravenous catheter (20G)</td>
			<td>Terumo</td>
			<td>SR-OT2051C</td>
			<td>Surgical expendables</td>
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		<tr>
			<td>Isoflurane</td>
			<td>Fujifilm</td>
			<td>095-06573</td>
			<td>Anesthesia</td>
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		<tr>
			<td>Lidocaine hydrochloride</td>
			<td>MP Biomedicals</td>
			<td>193917</td>
			<td>Anesthesia</td>
		</tr>
		<tr>
			<td>Pentobarbital sodium</td>
			<td>Tokyo Chemical Industry</td>
			<td>P0776</td>
			<td>Anesthesia</td>
		</tr>
	</tbody>
</table>

a rabbit venous interposition model mimicking revascularization surgery using vein grafts to assess intimal hyperplasia under arterial blood pressure

虽然静脉移植在缺血性疾病的再血管化手术中通常用作自体移植物，但由于动脉血压暴露，导致静脉增生加速，长期的体量仍然很差。本协议旨在通过将兔形静脉与ipsi侧胡萝卜动脉相交，建立实验性静脉增生。该协议不需要在身体躯干深处进行外科手术，切口的程度有限，对动物的侵入性较小，允许在植入后进行长期观察。这个简单的程序使研究人员能够研究减轻植入静脉移植的暗示增生进展的策略。使用这种协议，我们报告了微RNA-145（miR-145）的影响转导，已知微RNA-145能够控制血管平滑肌肉细胞（VSMC）从增殖到收缩状态的表型，进入收获的静脉移植物。我们通过VSMC的表型变化，在植入手术前通过转导miR-145，证实了静脉移植的体内增生衰减。在这里，我们报告一个侵入性较低的实验平台，以研究可用于减轻静脉移植在再血管手术中的风险增生的策略。

图 1A显示了静脉间位手术（上面板）后 2 周内成功进行插值增生的代表性图像。下面板显示微RNA-145负载聚（乳酸-共甘油酸）纳米粒子的治疗效果，这些纳米粒子衰减了内量增生（下面板）。图1B显示了使用磷酸盐缓冲盐水控制（PBS）、控制微RNA（Cont-miR）和微RNA-145（miR-145）组对照组之间的内量增生的比较。微RNA含有聚（乳酸-共甘油酸）纳米粒子。微R...

Watch this Scientific Journal Video about A Rabbit Venous Interposition Model Mimicking Revascularization Surgery using Vein Grafts to Assess Intimal Hyperplasia under Arterial Blood Pressure at JoVE.

A Rabbit Venous Interposition Model Mimicking Revascularization Surgery using Vein Grafts to Assess Intimal Hyperplasia under Arterial Blood Pressure

本议定书旨在通过将静脉置于动脉血压下，在使用静脉移植进行静脉移植手术后衰减静脉内血性增生的策略，从而在实验中产生静脉内质增生。

兔子静脉介词模型模仿再血管化手术使用静脉移植评估动脉血压下的影响增生

Although vein grafts have been commonly used as autologous grafts in revascularization surgeries for ischemic diseases, the long-term patency remains poor ...

我们的协议为静脉刺激增生领域的研究人员提供了一个简单、经济高效、可重复和临床相关的模型。我们的协议在经济上、临床上和技术上都是平衡的。因此，强烈建议那些希望将其体外结果应用于体内环境的研究人员。我们相信，我们的协议可以应用于一个更大的动物模型，以开发新的治疗策略，在缺血性心脏和下肢疾病。我们的协议主要与心血管手术领域有关。然而，它也可用于解决动脉静脉管炎的退行性变化在患者的末期肾病。局部麻醉后，预防性抗生素镇痛剂给药，用10%的波维多碘对手术现场进行消毒。并在麻醉的雄性日本白兔的颈椎区域用手术刀切口50至60毫米。模糊解剖皮下组织和筋膜，露出20至30毫米的血管段。并使用 4-0 丝缝合线将暴露静脉的所有分支都缝合。在静脉的内脏和外静脉周围放置一个2-0丝状缝合，并在静脉的静脉壁上做一毫米切口。插入一个2-法国气球导管从切口向静脉的近端。并在壶静脉的上将 2 - 0 的丝绸缝合线。用200微升的空气充气气球。并使用气球三次使静脉内皮去角质。第三次通过后，将静脉的近端进行开盖，并在端点切开静脉。然后插入20量表静脉导管到收获的静脉从远向近向，并在近位点切割静脉。要将胡萝卜动脉与收获的血管进行插管，请露出20至30毫米的静脉胡萝卜动脉。小心地将动脉与附近的静脉和神经分开。用 4 - 0 丝缝合将裸露静脉的所有分支都拉起。并静脉注射200国际单位每公斤肝素钠。用手术橡胶夹夹住动脉的近端和近端。切开夹子之间的动脉将正常的盐水直接注入切开的胡萝卜动脉，以分散动脉。将收获静脉放在动脉附近，以反向的端到端方式使血管变化。将静脉的近端对动脉的端端进行麻醉，放置两个 8-0 的锚缝聚丙烯在站点和对面的站点。在锚缝之间添加麻醉线的上侧。翻转动脉和静脉移植倒置。并在动脉瘤线的剩余部分添加缝合。接下来，从静脉中取出静脉导管，并紧接静脉移植。将胡萝卜动脉的灯对地开脱。观察静脉移植是否逐渐扩大。使用 8-0聚丙烯中断缝合，将静脉的端到动脉的近端。并给动脉下灯，检查动脉瘤部位的出血。最后，用4-0丝线缝合将内胡萝卜状动脉装开，以模拟不良的径流状况，促进刺激性增生。然后用盐水清洁伤口。用3-0聚加糖910层关闭切口。并允许兔子完全恢复监测之前，返回动物回家的笼子。在这个具有代表性的图像中，可以观察到静脉间穿手术后2周成功的刺激性增生。在这里，可以观察到微RNA-145加载的多（乳酸共糖酸）纳米粒子对刺激性增生形态的治疗效果。事实上，使用含有聚（乳酸共糖酸）的微RNA进行治疗，可显著衰减内刺激性增生。此外，Ki-67（细胞增殖标记物）的免疫抑制显示微RNA-145治疗组内的Ki-67阳性细胞较少，表明血管平滑肌细胞的表型变化从不成熟的增殖状态到成熟的收缩状态。我们协议的主要目标是实现植入移植物的可移植性。同样重要的是，要确认移植物在脱脱了胡萝卜动脉后会扩大。

Research

JoVE Journal

Medicine

Microsurgical Venous Pouch Arterial-Bifurcation Aneurysms in the Rabbit Model: Technical Aspects

显微静脉袋分岔动脉瘤在兔模型：技术问题

For ruptured human cerebral aneurysms endovascular embolization has become an equivalent alternative to aneurysm clipping.1 However, large clinical trials ...

科研

医学

Electrolytic Inferior Vena Cava Model (EIM) of Venous Thrombosis

Electrolytic Inferior Vena Cava Model EIM of Venous Thrombosis

电解下腔静脉静脉血栓形成的模型（EIM）

Animal models serve a vital role in deep venous thrombosis (DVT) research in order to study thrombus formation, thrombus resolution and to test potential ...

Femoral Arterial and Venous Catheterization for Blood Sampling, Drug Administration and Conscious Blood Pressure and Heart Rate Measurements

股动脉和静脉导管采血，药品监督管理局和意识的血压和心率测量

In multiple fields of study, access to the circulatory system in laboratory studies is necessary. Pharmacological studies in rats using chronically ...

Training a Sophisticated Microsurgical Technique: Interposition of External Jugular Vein Graft in the Common Carotid Artery in Rats

培养一个精密的显微外科技术在大鼠颈总动脉，颈外静脉移植：介入

Neointimal hyperplasia is one the primary causes of stenosis in arterialized veins that are of great importance in arterial coronary bypass surgery, in ...

Adult Mouse Venous Hypertension Model: Common Carotid Artery to External Jugular Vein Anastomosis.

成年小鼠静脉高压型号：颈总动脉，以颈外静脉吻合。

The understanding of the pathophysiology of brain arteriovenous malformations and arteriovenous fistulas has improved thanks to animal models. A rat model ...

Vein Interposition Model: A Suitable Model to Study Bypass Graft Patency

静脉介入型号：研究旁路移植通畅一个合适的模型

Bypass grafting is an established treatment method for coronary artery disease. Graft patency continues to be the Achilles heel of saphenous vein grafts. ...

Using the Sleeve Technique in a Mouse Model of Aortic Transplantation - An Instructional Video

套筒技术在主动脉移植小鼠模型中的应用-教学视频

Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the ...

A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

应用 Ameroid 的猪慢性心肌缺血模型

Cardiovascular disease remains the number one cause of mortality in the United States. There are numerous approaches to treating these diseases, but ...

A Rabbit Model of Durable Transgene Expression in Jugular Vein to Common Carotid Artery Interposition Grafts

颈动脉介入移植中颈静脉持久性转基因表达的家兔模型

Vein graft bypass surgery is a common treatment for occlusive arterial disease; however, long-term success is limited by graft failure due to thrombosis, ...

Murine Model of Central Venous Stenosis using Aortocaval Fistula with an Outflow Stenosis

中央静脉狭窄病的Murine模型,使用具有流出狭窄病的动脉静脉瘘管病

Central venous stenosis is an important entity contributing to arteriovenous fistula (AVF) failure. A murine AVF model was modified to create a partial ...