The work was supported by the intramural research program of the NIH, National Institute on Aging, and by a Priority Research Centers Program grant from the National Research Foundation (NRF-2009-0093812) funded by the Ministry of Science, Information and Communication Technology, &amp; Future Planning, the Republic of Korea (H.T.). We thank Dr. Han-sol Park for putting "material" part together for the manuscript.

注:采用大鼠球囊损伤模型，包括重组的sRAGE和超声声像图的研究注入相关手续已通过国家研究所的动物护理和使用委员会（ACUC）老龄，美国国立卫生研究院。 1.手术前的准备工作<ol><li>仪器，手术平台和个人防护装备。 <ol><li>见材料和设备的表都在这个过程中使用的手术器械和试剂。高压灭菌前，手术过程中的所有手术器械。 注:对于在同一天进行多次手术，使用预先加热的玻璃珠灭菌消毒手术之间的仪器。 </li><li>消毒操作平台，用70％的醇的表面上。换上手术衣，发​​罩，口罩，防护眼镜和手套。离开无菌手套一箱附近的手术平台，为更多的美国即</li></ol></li><li>球囊导管的研制。 <ol><li>填充1ml注射器用无菌水和注射器连接到无菌充水双向旋塞。轻轻通过活栓推动水来填充囊导管的鲁尔锁定部，并从该导管的开口去除气泡。 </li><li>测试球囊扩张，以确保气囊可以0.02毫升水充气。储存气囊的前端在灭菌水容器中的手术前，以避免干燥和污染。 </li></ol></li><li>麻醉和动物的制备。 <ol><li>称取雄性Wistar大鼠（400-450克），检查耳标，确认ID。将大鼠在感应室，然后打开蒸发器和调节异氟醚水平3.5-4.0％，而氧气含量1.5-2.0 L.通过检查踏板撤回反射，如捏脚趾或尾部检查镇静的深度的动物。 </li><li>到达麻醉后（ <em&gt;即动物缺乏踏板撤回反射），动物转移到外科平台，并与一个连接到麻醉汽化器鼻锥钩大鼠。调整异氟醚浓度1.5-2.0和氧气0.6-1.0 L.定期按捏动物的脚趾或尾部，以保证大鼠是完全放松和不动的检查镇静的深度。 </li><li>达到麻醉的手术水平之后，从下巴剃腹侧颈部区域下降到刚刚与动物毛发推剪胸骨上方并具有交替的1:10稀释的聚维酮碘和70％乙醇3次的擦拭剃光皮肤。 </li><li>放置在用棉签动物的睁眼用溶液，以防止它们干燥。滋润动物的舌头和口腔饮用水，以避免在操作过程中干燥。 </li><li>覆盖用无菌手术片大鼠和切割片材，以暴露颈区域。将在仰卧位澳动物呐加热手术平台的头朝着外科医生垫。固定动物的肢体使用磁带手术平台。 </li></ol></li></ol> 2.外科手术<ol><li>解剖和左颈动脉分离<ol><li>使用手术刀使下巴下方的直切口的方向朝向尾一路胸骨正上方的肋笼的顶部。使用7S钳直言不讳地剖析皮肤下的唾液腺腺体组织揭露肌层。单独的肌肉组织，以获得颈动脉血管，并在颈部区域中的迷走神经。 </li><li>直截了当地解剖围绕颈动脉的组织，并仔细分离迷走神经和血管筋膜，以避免任何损坏。不断解剖直到颈动脉分叉以暴露内部和外部的分支和颈总动脉向下到胸骨。 </li></ol></li><li> Arteriot的制备OMY <ol><li>退回和止血，放置在上左颈总动脉的最接近部位的结扎，并在该位置立即远离分叉另一个结扎。 </li><li>放置在颈外动脉一4.0丝线从分叉尽可能远缩回向头部的动脉。永久结扎用4.0丝缝合沿着颈外动脉包括咽升，枕部和甲状腺避免动脉泄漏小动脉。 </li><li>周围放置颈内动脉中的4.0丝缝合避免显著逆行血液损失。通常，内部分支的可用长度是最小的。为了显现颈内动脉，暴露出内部颈动脉尽可能多轻轻缩回覆颈动脉到右侧。 </li></ol></li><li>球囊导管的介绍<ol><li>缩回在颈总一个近侧缝合线rtery和放置在容器中的动脉夹钳暂时停止血液流动。使一个小的（1/3到动脉的圆周的1/4）的颈外动脉切口的位置处作为远端的缝合线越好。 </li><li>轻轻插入的未充气气囊导管进入切口，然后推进导管在管腔靠近在颈总动脉的动脉夹钳。除去夹子，并且进一步推进囊导管的主动脉弓，从切口大约35-40毫米。 </li></ol></li><li>球囊损伤<ol><li>手动充气导管经由附注射器0.02毫升一个体积，然后锁定所述注射器和导管之间的活塞。用旋转慢慢撤出导管。当导管靠近arteriotomic切口，放气的气球。推进导管回原来的位置。 </li><li>重复2.4.1共3次。小心地从动脉腔内取出导管。 </li></ol></li><li>收上来的外科伤口<ol><li>关闭缝合动脉切开术。释放内颈动脉，以恢复血流。检查动脉出血或渗漏。如果发生出血，应用纱布带着几分压力止血。 </li><li>除去用于程序缝线和夹子的其余部分。 6.0缝合关闭腺体组织。关闭与皮肤缝合伤口或剪辑皮肤。关闭异氟醚和留下纯氧动物几分钟。 </li></ol></li></ol> 3.治疗管理，止痛药，手术后护理和安乐死<ol><li>治疗和止痛药的管理。 <ol><li>继手术，（0.03毫克/千克）肌内注射丁丙诺啡。注入5毫升预温热的无菌盐水皮下的手术过程中以补偿血液损失。注入的sRAGE（0.5纳克/克）（治疗剂）插入腹膜。 </li><li>与OPH再次滋润眼睛thalmic软膏。广场上的隔热垫鼠和监控动物，直到它完全恢复了意识，以保持胸骨斜卧。 </li><li>返回老鼠有干净的被褥笼子，把笼子回到动物饲养。放置在笼子里的特别观察卡提醒与会兽医和照顾。 </li></ol></li><li>手术后清理<ol><li>把手术用的材料，包括垫，棉签，针头等人要么扔进垃圾桶或特殊处理容器。消毒手术平台并清洁手术器械。 </li></ol></li><li>手术后护理<ol><li>管理在48小时后手术期间丁丙诺啡（0.03毫克/公斤），每天两次（BID）。在48小时后手术期间窘迫的常见的症状，如不动，无力养活，hutched姿势，皱皮，和扮鬼脸，密切监视动物。监测红肿伤口情况，肿胀，开裂，和感染。 注意:额外的治疗可根据主治兽医的建议规定。 </li><li>据主治兽医的建议拆除缝线或伤口剪辑。 </li></ol></li><li>安乐死<ol><li>手术后两周，安乐死大鼠分离颈动脉为验尸HISTO形态学分析22。放置老鼠在含有5-20％的异氟醚的饱和空气中至少2分钟，直到呼吸完全停止的腔室。确认死亡的器官和组织的解剖前。 </li></ol></li></ol>

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作者宣称，他们没有竞争的经济利益。

已经有用于充气气球以产生，消除在颈动脉管腔壁画内皮损伤的两种方法。之一是用液体20填充附注射器，而另一种是使用空气压力21。我们更喜欢使用液体填充的注射器，因为确切的液体体积（0.02毫升）将用于每个过程。这使得该气球的精确和可重复的通货膨胀，导致损伤的每只动物接受的过程的类似水平。在注射器中使用的液体确实需要在液体去除气泡。这可以通过从导管的开口推动气泡出来而实现。除去大部分的气泡后，任何残留的，微小的气泡会在1-2小时消散。我们建议，研究人员使手术前材料准备步骤之前1-2小时，并且每个单独的外科手术，以保证Appro公司之前检查球囊扩张的程度priate通货膨胀。 对于手术，外科医生和他/她的助手（多个）必须穿所有必要的保护装备，包括面罩，无菌手套，和外科手术衣，以保护动物和研究人员免受感染。 （ 如 380-450 g的），以确保颈动脉用于此过程引入标准2F Fogarty的气球导管取栓术的正确尺寸是使用完全成熟，雄性大鼠具有类似bodyweights重要。在手术前，检查异氟醚的水平在汽化器，以确保覆盖整个手术的麻醉剂的足够量的，并且每个手术开始前，如果有必要重新填充汽化器。检查氧气罐的压力表以确保手术足够的氧气。以确保达到麻醉的适当深度，还可以监测大鼠的呼吸频率。正常大鼠有〜85呼吸/ min的呼吸频率;增加的呼吸深度和再gular节奏，和呼吸率的下降意味着外科麻醉。 在手术过程中，麻醉必须连续监测并通过检查呼吸，踏板反射，和动物的到手术刺激的反应保持。值得注意的是，外科医生应该改变手套如果他/她的手在手术过程中按动物的非无菌部分如检查踏板反射以防止潜在的污染和感染。此外，外科医生和助手也应仔细监测操作过程中动物的生命体征，防止麻醉过量，如果发生通过关闭异氟醚它迅速采取纠正措施，以避免形势，增加氧气含量为100％。麻醉剂过量的症状包括慢而浅的呼吸，而弱和不规则的脉搏。我们还建议做好准备动脉切开的球囊损伤之前，包括颈动脉一个完全分离从邻近组织rtery部分。这将有助于在操作过程中，以避免意外的出血。 麻醉下的动物，包括在手术后恢复阶段，不应该被看管。作为替代在48小时后手术期间经常丁丙诺啡（0.03毫克/公斤的出价），持续释放叔丁啡（丁丙诺啡SR）也可以使用。手术后立即SR丁丙诺啡（1.0-1.2毫克/千克）的注入将覆盖手术后的一段长达72小时。一般情况下，术后并发症没有预料到的;但细心的监察的做法保证了动物的福利，是制度ACUC的政策。 因为它重现研究组的动物（8-15），适当的手术技能，并与程序熟悉在气球伤害的同一水平是最重要的是高度推荐的。对于新研究员此过程中，我们建议第一练习包括准备动脉切开术的，气球伤害和对大鼠的屠体可能在体制动物设施是可用的伤口闭合的整个过程。与执业兽医或研究人员熟悉的过程手术过程也确保获得可重复性和一致性球囊损伤的结果。 我们认为，药物和/或否定新内膜生长的治疗剂，最好立即球囊损伤后，以便在早期阶段，以抵消炎症给药。某些试剂可能需要在恢复的随后的日子连续施用达到的效果。早期干预有助于阻止或减少随后的血管重塑13,22,24。

血管成形术是用于加宽狭窄或阻塞的动脉从病理状况例如动脉粥样硬化所得的血管内手术。血管成形术的一种常见并发症是后期运营内膜增生，或再狭窄，发生由于手术伤害和随后的炎症引起的血管重塑。这些条件导致血管平滑肌细胞和多种病理生理后果1-3的增殖。新内膜增生再变稠容器中，并发生在高达60％的血管成形术后的患者的第一年之内。因此，再狭窄是广泛使用的血管成形术4的重大挫折。虽然药物洗脱支架植入可能有助于防止再狭窄，唯一入选的考生可以接受这种昂贵的步骤5。 动物和临床研究中已经确定，通过vascu产生慢性炎症LAR伤害和/或手术伤口用作血管成形术后内膜生长2,4主要刺激。大鼠颈动脉损伤模型模拟临床情况，因此作为一个有价值的模型系统识别，在血管重构和血管细胞增殖6-9涉及的细胞因子。该模型系统也是评价一个非常有用的工具和/或屏幕为抑制在临床前翻译研究10-14新内膜生长的药物和治疗的试剂。 相较于小鼠颈动脉导线损伤模型15和小鼠股动脉导线损伤模型16，大鼠颈球囊损伤模型中是规模足够大，便于手术操作，便于对造成的伤害的可重复性的优势。它可以提供原代细胞为ADDIT更大数目（ 例如 ，血管平滑肌细胞，内皮细胞）有理体外研究来描绘理事血管重塑的分子机制。重要的是，相对于小鼠，大鼠也已知可用于生理和毒理学研究17更好的模型。虽然大鼠模型的缺点或限制是缺乏遗传改良和基因敲除模型，这个缺点可以通过大鼠基因组序列的可用性以及最近强大的基因组编辑工具，如CRISPR-CAS技术，使发展来克服在不同的模型系统18,19基因组序列的广大范围可能操纵。 虽然大鼠球囊损伤模型已被用于多个实验室和各种综合性协议已经公布的20,21，这个协议的目的是在手术前的准备工作，提供更多的细节，可以引导研究人员新的这个步骤设置这种手术的做法。我们还强调，手术后护理的t他的动物，允许未对动脉重塑的治疗效果只有验尸病理组织形态学和分析，也超声声像图研究活体动物13,22。

<table><tbody><tr><td>2 F Fogarty balloon embolectomy catheter&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td>Edwards Lifesciences&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Standard scalpel</td><td>Fine Science Tools</td><td></td><td></td></tr><tr><td>Small&amp;nbsp; curved forceps (Large radius Dumont#7shanks curved)&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Large, medium and small micro-scissors</td><td>Roboz</td><td></td><td></td></tr><tr><td>Needles (20 G)&amp;nbsp;&amp;nbsp;</td><td>TycoHealthcare</td><td></td><td></td></tr><tr><td>Micro-surgery forceps with micro-blunted atraumatic tips</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Atraumatic straight small arterial clamps&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Retractor&amp;nbsp; with maximum spread 5.5 cm long blunt teeth</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Silk suture (4.0 and&amp;nbsp; 6.0 )</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>Syringe (1.0 ml)&amp;nbsp;</td><td>BD&amp;nbsp;</td><td></td><td></td></tr><tr><td>Curity gauze sponges</td><td>AllegroMedical</td><td></td><td></td></tr><tr><td>Cotton tip applicators sterile and non-sterile</td><td>Puritan Medical Products</td><td></td><td></td></tr><tr><td>Compact hot bead sterilizer</td><td>Fine Science Tools</td><td></td><td></td></tr><tr><td>Self-regulating heating pad</td><td>Fine Science Tools&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td></td><td></td></tr><tr><td>ADS200 anesthesia system/ventilator</td><td>Paragon Medical</td><td></td><td></td></tr><tr><td>Isoflurane (forane), liquid form</td><td>Baxter</td><td></td><td></td></tr><tr><td>Sodium chloride 0.9% (Saline)&amp;nbsp;</td><td>Hospira</td><td></td><td></td></tr><tr><td>Buprenex (buprenorphine)&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;</td><td>Reckitt Benckiser Healthcare (UK) Ltd.&amp;nbsp;</td><td></td><td></td></tr><tr><td>70% alcohol</td><td>Fisher</td><td></td><td></td></tr><tr><td>1:10 Betadine</td><td>Fisher</td><td></td><td></td></tr></tbody></table>

a rat carotid balloon injury model to test anti-vascular remodeling therapeutics

The rat carotid balloon injury is a well-established surgical model that has been used to study arterial remodeling and vascular cell proliferation. It is also a valuable model system to test, and to evaluate therapeutics and drugs that negate maladaptive remodeling in the vessel. The injury, or barotrauma, in the vessel lumen caused by an inflated balloon via an inserted catheter induces subsequent neointimal growth, often leading to hyperplasia or thickening of the vessel wall that narrows, or obstructs the lumen. The method described here is sufficiently sensitive, and the results can be obtained in relatively short time (2 weeks after the surgery). The efficacy of the drug or therapeutic against the induced-remodeling can be evaluated either by the post-mortem pathological and histomorphological analysis, or by ultrasound sonography in live animals. In addition, this model system has also been used to determine the therapeutic window or the time course of the administered drug. These studies can leadto the development of a better administrative strategy and a better therapeutic outcome. The procedure described here provides a tool for translational studies that bring drug and therapeutic candidates from bench research to clinical applications.

气囊损伤后两周，将大鼠安乐死并颈动脉被隔离HISTO形态学分析。这两种操作左侧颈总动脉和非经营右动脉的横截面，处理和石蜡包埋。石蜡样品然后进一步薄切片，并用苏木精 - 曙红（H＆E）染色。 HISTO形态学分析是使用数字成像分析系统进行。动脉收获及组织形态学分析的细节已被描述13,23。球囊损伤引起新内膜生长，或血管壁的变厚，如果不进行治疗（或用生理盐水作为安慰剂处理）， 如图1B中可以看出，与从同一大鼠非操作容器部（ 图1A）。从大鼠接收治疗试剂容器部分（在这种情况下，与sRAGE），该块内膜生长表明significantly减少血管壁（ 图1C）的增厚。气囊损伤的效果以及治疗性处理也可以在体内使用超声波超声22，其与来自HISTO形态学分析的结果协作井（ 图2）进行评价。对于功效的评价和治疗的sRAGE在大鼠球囊损伤模型的管理窗口的细节已在以前的出版物13,22进行了描述。为了评价降低或阻断损伤引起血管壁重塑治疗试剂，一组大鼠（N = 8-15）是为了得到统计上有意义的结论，以进行操作。 <img alt="图1" src="/files/ftp_upload/53777/53777fig1.jpg" /> 图 1:在caroti 从大鼠颈球囊损伤模型代表性的成果 H＆E染色ð动脉的横截面（A）的非操作右颈动脉部; （B）中的球囊损伤和安慰剂治疗的左颈动脉部分（箭头表示neotimal区域）; （C）气球受伤的sRAGE处理左颈动脉部分。 <a href="https://www.jove.com/files/ftp_upload/53777/53777fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/53777/53777fig2.jpg" /> 图 2:在2周后的损伤（在从（A）中的数据的散点图管腔直径和（B）血管壁的厚度示出超声超声和组织学的相关性的sRAGE（0.5纳克/克）处理颈动脉血管的非操作，具有与sRAGE受伤，安慰剂组，每组12个）。 （C）代表sonographic和组织学（100X）的图像。 （图来自参考22，与出版商的许可）。 <a href="https://www.jove.com/files/ftp_upload/53777/53777fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about A Rat Carotid Balloon Injury Model to Test Anti-vascular Remodeling Therapeutics at JoVE.com

A Rat Carotid Balloon Injury Model to Test Anti-vascular Remodeling Therapeutics

The rat carotid balloon injury model described below allows researchers to evaluate drugs or therapeutics that negate injury-induced arterial hyperplasia. Detailed pre-surgical preparation, surgical procedure, and post-surgical cares of the animal are described.

大鼠颈动脉球囊损伤模型试验抗血管重建治疗

The rat carotid balloon injury is a well-established surgical model that has been used to study arterial remodeling and vascular cell proliferation. It is ...

a-rat-carotid-balloon-injury-model-to-test-anti-vascular-remodeling

Nanyang Technological University

Research

JoVE Journal

Medicine

8.7K 次观看.  National Institute on Aging. The rat carotid balloon injury model described below allows researchers to evaluate drugs or therapeutics that negate injury-induced arterial hyperplasia. Detailed pre-surgical preparation, surgical procedure, and post-surgical cares of the animal are described. 

视频: A Rat Carotid Balloon Injury Model to Test Anti-vascular Remodeling Therapeutics

A Model of Disturbed Flow-Induced Atherosclerosis in Mouse Carotid Artery by Partial Ligation and a Simple Method of RNA Isolation from Carotid Endothelium

Despite the well-known close association, direct evidence linking disturbed flow to atherogenesis has been lacking. We have recently used a modified version of carotid partial ligation methods [1,2] to show that it acutely induces low and oscillatory flow conditions, two key characteristics of disturbed flow, in the mouse common carotid artery. Using this model, we have provided direct evidence that disturbed flow indeed leads to rapid and robust atherosclerosis development in Apolipoprotein E knockout mouse [3]. We also developed a method of endothelial RNA preparation with high purity from the mouse carotid intima [3]. Using this mouse model and method, we found that partial ligation causes endothelial dysfunction in a week, followed by robust and rapid atheroma formation in two weeks in a hyperlipidemic mouse model along with features of complex lesion formation such as intraplaque neovascularization by four weeks. This rapid in vivo model and the endothelial RNA preparation method could be used to determine molecular mechanisms underlying flow-dependent regulation of vascular biology and diseases. Also, it could be used to test various therapeutic interventions targeting endothelial dysfunction and atherosclerosis in considerably reduced study duration.

This describes a partial carotid ligation surgery, which causes disturbed flow conditions and subsequent atherosclerosis development (in two weeks) with intraplaque neo-vascularization (in four weeks) in the mouse common carotid artery. We also describe a novel method of RNA isolation from the carotid intima, providing high purity endothelial RNA.

一个型号的不安流致动脉粥样硬化小鼠颈动脉部分结扎术和颈动脉内皮细胞的RNA分离的简单方法

Despite the well-known close association, direct evidence linking disturbed flow to atherogenesis has been lacking. We have recently used a modified ...

科研

医学

Murine Spinotrapezius Model to Assess the Impact of Arteriolar Ligation on Microvascular Function and Remodeling

The murine spinotrapezius is a thin, superficial skeletal support muscle that extends from T3 to L4, and is easily accessible via dorsal skin incision. Its unique anatomy makes the spinotrapezius useful for investigation of ischemic injury and subsequent microvascular remodeling. Here, we demonstrate an arteriolar ligation model in the murine spinotrapezius muscle that was developed by our research team and previously published1-3. For certain vulnerable mouse strains, such as the Balb/c mouse, this ligation surgery reliably creates skeletal muscle ischemia and serves as a platform for investigating therapies that stimulate revascularization. Methods of assessment are also demonstrated, including the use of intravital and confocal microscopy. The spinotrapezius is well suited to such imaging studies due to its accessibility (superficial dorsal anatomy) and relative thinness (60-200 &mu;m). The spinotrapezius muscle can be mounted en face, facilitating imaging of whole-muscle microvascular networks without histological sectioning. We describe the use of intravital microscopy to acquire metrics following a functional vasodilation procedure; specifically, the increase in arterilar diameter as a result of muscle contraction. We also demonstrate the procedures for harvesting and fixing the tissues, a necessary precursor to immunostaining studies and the use of confocal microscopy.

We demonstrate a novel arterial ligation model in murine spinotrapezius muscle, including a step-by-step procedure and description of required instrumentation. We describe the surgery and relevant outcome measurements relating to vascular network remodeling and functional vasodilation using intravital and confocal microscopy.

小鼠Spinotrapezius模型来评估的影响小动脉结扎​​术，微血管功能与重塑

The murine spinotrapezius is a thin, superficial skeletal support muscle that extends from T3 to L4, and is easily accessible via dorsal skin incision. ...

A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis

Despite the considerable progress made in the stent development in the last decades, cardiovascular diseases remain the main cause of death in western countries. Beside the benefits offered by the development of different drug-eluting stents, the coronary revascularization bears also the life-threatening risks of in-stent thrombosis and restenosis. Research on new therapeutic strategies is impaired by the lack of appropriate methods to study stent implantation and restenosis processes. Here, we describe a rapid and accessible procedure of stent implantation in mouse carotid artery, which offers the possibility to study in a convenient way the molecular mechanisms of vessel remodeling and the effects of different drug coatings.

A model of stent implantation in mouse carotid artery is described. Compared to other similar methods, this procedure is very rapid, simple and accessible, offering the possibility to study in a convenient way the vascular wall reaction to different drug-eluting stents and the molecular mechanisms of restenosis.

颈动脉支架植入再狭窄的研究的小鼠模型

Despite  the considerable progress made in the stent development in the last decades,  cardiovascular diseases remain the main cause of death in western ...

Vascular Balloon Injury and Intraluminal Administration in Rat Carotid Artery

The carotid artery balloon injury model in rats has been well established for over two decades. It remains an important method to study the molecular and cellular mechanisms involved in vascular smooth muscle dedifferentiation, neointima formation and vascular remodeling. Male Sprague-Dawley rats are the most frequently employed animals for this model. Female rats are not preferred as female hormones are protective against vascular diseases and thus introduce a variation into this procedure. The left carotid is typically injured with the right carotid serving as a negative control. Left carotid injury is caused by the inflated balloon that denudes the endothelium and distends the vessel wall. Following injury, potential therapeutic strategies such as the use of pharmacological compounds and either gene or shRNA transfer can be evaluated. Typically for gene or shRNA transfer, the injured section of the vessel lumen is locally transduced for 30 min with viral particles encoding either a protein or shRNA for delivery and expression in the injured vessel wall. Neointimal thickening representing proliferative vascular smooth muscle cells usually peaks at 2 weeks after injury. Vessels are mostly harvested at this time point for cellular and molecular analysis of cell signaling pathways as well as gene and protein expression. Vessels can also be harvested at earlier time points to determine the onset of expression and/or activation of a specific protein or pathway, depending on the experimental aims intended. Vessels can be characterized and evaluated using histological staining, immunohistochemistry, protein/mRNA assays, and activity assays. The intact right carotid artery from the same animal is an ideal internal control. Injury-induced changes in molecular and cellular parameters can be evaluated by comparing the injured artery to the internal right control artery. Likewise, therapeutic modalities can be evaluated by comparing the injured and treated artery to the control injured only artery.

This protocol uses a balloon catheter to cause an intraluminal injury on the rat carotid artery and henceforth elicit neointimal hyperplasia. This is a well-established model for studying the mechanisms of vascular remodeling in response to injury. It is also widely used to determine the validity of potential therapeutic approaches.

血管球囊损伤和腔内管理在大鼠颈动脉

The carotid artery balloon injury model in rats has been well established for over two decades. It remains an important method to study the molecular and ...

Murine Model of Femoral Artery Wire Injury with Implantation of a Perivascular Drug Delivery Patch

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. While these therapies lead to the rapid restoration of blood flow, these technologies remain limited by restenosis in the case of bare metal stents and angioplasty, or reduced healing and possibly enhanced risk of thrombosis in the case of drug eluting stents. A key pathophysiological mechanism in the formation of restenosis is intimal hyperplasia caused by the activation of vascular smooth muscle cells and inflammation due to arterial stretch and injury. Surgeries that induce arterial injury in genetically modified mice are useful for the mechanistic study of the vascular response to injury but are often technically challenging to perform in mouse models due to the their small size and lack of appropriate sized devices. We describe two approaches for a surgical technique that induces endothelial denudation and arterial stretch in the femoral artery of mice to produce robust neointimal hyperplasia. The first approach creates an arteriotomy in the muscular branch of the femoral artery to obtain vascular access. Following wire injury this arterial branch is ligated to close the arteriotomy. A second approach creates an arteriotomy in the main femoral artery that is later closed through localized cautery. This method allows for vascular access through a larger vessel and, consequently, provides a less technically demanding procedure that can be used in smaller mice. Following either method of arterial injury, a degradable drug delivery patch can be placed over or around the injured artery to deliver therapeutic agents.

We describe a surgical technique that produces wire injury in the femoral artery of mice to induce neointimal hyperplasia to serve as a model testing system for the perivascular delivery of therapeutic compounds for the inhibition of restenosis.

股动脉线损伤的小鼠模型的血管周围给药补丁植入

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. ...

Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model

Atherosclerosis is a proliferative fibro-inflammatory disease developing in the arterial wall, inducing a deficient blood flow or a lack of blood flow. Moreover, by rupture of the defective vascular wall, atherosclerosis induces occlusive thrombus formation, which represents the main cause of myocardial infarction or stroke and the most frequent cause of death. Despite the advances in the cardiovascular field, many questions remain unanswered, and additional basic research is essential to improve our understanding of the molecular mechanisms during atherosclerosis and its effects. Due to limited clinical studies, there is a need for representative animal models recreating atherosclerotic conditions such as neointima formation after stent implantation, balloon angioplasty, or endarterectomy. Since the mouse presents many advantages and is the most frequently used model for studying molecular processes, the current study proposes an invasive procedure of endothelial denudation, also known as the wire-injury model, which is representative of the human condition of neointima formation in arteries after revascularization procedures.

This study describes an invasive procedure for the induction of accelerated atherosclerosis in mice. In comparison to other methods using electric- or cryo-induced injury, mechanical-induced injury mimics the human condition of restenosis after revascularization therapies and is ideal for the study of the molecular mechanisms involved.

小鼠加速动脉硬化的诱导:"电线损伤"模型

Atherosclerosis is a proliferative fibro-inflammatory disease developing in the arterial wall, inducing a deficient blood flow or a lack of blood flow. ...

Reproducible Arterial Denudation Injury by Infrarenal Abdominal Aortic Clamping in a Murine Model

Percutaneous vascular interventions uniformly result in arterial denudation injuries that subsequently lead to thrombosis and restenosis. These complications can be attributed to impairments in re-endothelialization within the wound margins. Yet, the cellular and molecular mechanisms of re-endothelialization remain to be defined. While several animal models to study re-endothelialization after arterial denudation are available, few are performed in the mouse because of surgical limitations. This undermines the opportunity to exploit transgenic mouse lines and investigate the contribution of specific genes to the process of re-endothelialization. Here, we present a step-by-step protocol for creating a highly reproducible murine model of arterial denudation injury in the infrarenal abdominal aorta using external vascular clamping. Immunocytochemical staining of injured aortas for fibrinogen and &#946;-catenin demonstrate the exposure of a pro-thrombotic surface and the border of intact endothelium, respectively. The method presented here has the advantages of speed, excellent overall survival rate, and relative technical ease, creating a uniquely practical tool for imposing arterial denudation injury in transgenic mouse models. Using this method, investigators may elucidate the mechanisms of re-endothelialization under normal or pathological conditions.

Understanding the cellular and molecular mechanisms of re-endothelialization following arterial denudation injury is of paramount importance in preventing thrombosis and restenosis of arteries. Here we describe a protocol for reproducible arterial denudation injury of the infrarenal abdominal aorta. The procedure was developed to investigate the underlying mechanisms that regulate endothelial regeneration using mouse models.

重复性的动脉剥脱损伤腹主动脉阻断在小鼠模型

Percutaneous vascular interventions uniformly result in arterial denudation injuries that subsequently lead to thrombosis and restenosis. These ...

The Rabbit Model of Accelerated Atherosclerosis: A Methodological Perspective of the Iliac Artery Balloon Injury

Acute coronary syndrome resulting from coronary occlusion following atherosclerotic plaque development and rupture is the leading cause of death in the industrialized world. New Zealand White (NZW) rabbits are widely used as an animal model for the study of atherosclerosis. They develop spontaneous lesions when fed with atherogenic diet; however, this requires long time of 4 - 8 months. To further enhance and accelerate atherogenesis, a combination of atherogenic diet and mechanical endothelial injury is often employed. The presented procedure for inducing atherosclerotic plaques in rabbits uses a balloon catheter to disrupt the endothelium in the left iliac artery of NZW rabbits fed with atherogenic diet. Such mechanical damage caused by the balloon catheter induces a chain of inflammatory reactions initiating neointimal lipid accumulation in a time dependent fashion. Atherosclerotic plaque following balloon injury show neointimal thickening with extensive lipid infiltration, high smooth muscle cell content and presence of macrophage derived foam cells. This technique is simple, reproducible and produces plaque of controlled length within the iliac artery. The whole procedure is completed within 20 - 30 min. The procedure is safe with low mortality and also offers high success in obtaining substantial intimal lesions. The procedure of balloon catheter induced arterial injury results in atherosclerosis within two weeks. This model can be used for investigating the disease pathology, diagnostic imaging and to evaluate new therapeutic strategies.

Animal models of atherosclerosis are essential to understand the mechanism and to investigate newer approaches to prevent plaque development or rupture, a leading cause of death in the industrialized world. This protocol uses a combination of balloon injury and cholesterol rich diet to induce atherosclerotic plaques in rabbit iliac artery.

家兔加速动脉粥样硬化模型的研究--髂动脉球囊损伤的方法学观察

Acute coronary syndrome resulting from coronary occlusion following atherosclerotic plaque development and rupture is the leading cause of death in the ...

A Rat Carotid Artery Pressure-Controlled Segmental Balloon Injury with Periadventitial Therapeutic Application

Cardiovascular disease remains the leading cause of death and disability worldwide, in part due to atherosclerosis. Atherosclerotic plaque narrows the luminal surface area in arteries thereby reducing adequate blood flow to organs and distal tissues. Clinically, revascularization procedures such as balloon angioplasty with or without stent placement aim to restore blood flow. Although these procedures reestablish blood flow by reducing plaque burden, they damage the vessel wall, which initiates the arterial healing response. The prolonged healing response causes arterial restenosis, or re-narrowing, ultimately limiting the long-term success of these revascularization procedures. Therefore, preclinical animal models are integral for analyzing the pathophysiological mechanisms driving restenosis, and provide the opportunity to test novel therapeutic strategies. Murine models are cheaper and easier to operate on than large animal models. Balloon or wire injury are the two commonly accepted injury modalities used in murine models. Balloon injury models in particular mimic the clinical angioplasty procedure and cause adequate damage to the artery for the development of restenosis. Herein we describe the surgical details for performing and histologically analyzing the modified, pressure-controlled rat carotid artery balloon injury model. Additionally, this protocol highlights how local periadventitial application of therapeutics can be used to inhibit neointimal hyperplasia. Lastly, we present light sheet fluorescence microscopy as a novel approach for imaging and visualizing the arterial injury in three-dimensions.

The rat carotid artery balloon injury mimics the clinical angioplasty procedure performed to restore blood flow in atherosclerotic vessels. This model induces the arterial injury response by distending the arterial wall, and denuding the intimal layer of endothelial cells, ultimately causing remodeling and an intimal hyperplastic response.

大鼠胡萝卜动脉压力控制段气球损伤与腹腔ventit 治疗应用

Cardiovascular disease remains the leading cause of death and disability worldwide, in part due to atherosclerosis. Atherosclerotic plaque narrows the ...

Murine Aortic Crush Injury: An Efficient In Vivo Model of Smooth Muscle Cell Proliferation and Endothelial Function

Arterial reconstruction, whether angioplasty or bypass surgery, involves iatrogenic trauma causing endothelial disruption and vascular smooth muscle cell (VSMC) proliferation. Common murine models study small vessels such as the carotid and femoral arteries. Herein we describe an in vivo system in which both VSMC proliferation and endothelial barrier function can be simultaneously assessed in a large vessel. We studied the infrarenal aortic response to injury in C57BL/6 mice. The aorta was injured from the left renal vein to the aortic bifurcation by 30 transmural crushes of 5-seconds duration with a cotton-tipped applicator. Morphological changes were assessed with conventional histology. Aorta wall thickness was measured from the luminal surface to the adventitia. EdU integration and counter staining with DAPI and alpha-actin was used to demonstrate VSMC proliferation. Activation of ERK1/2, a known moderator of intimal hyperplasia formation, was determined by Western Blot analysis. The effect of inflammation was determined by immunohistochemistry for B-cells, T-cells, and macrophages. En face sections of endothelium were visualized with scanning electron microscopy (SEM). Endothelial barrier function was determined with Evans Blue staining. Transmural injury resulted in aortic wall thickening. This injury induced VSMC proliferation, most prominently at 3 days after injury, and early activation of ERK1/2 and decreased p27kip1 expression. Injury did not result in increased B-cells, T-cells, or macrophages infiltration in the vessel wall. Injury caused partial endothelial cell denudation and loss of cell-cell contact. Injury resulted in a significant loss of endothelial barrier function, which returned to baseline after seven days. The murine transmural blunt aortic injury model provides an efficient system to simultaneously study both VSMC proliferation and endothelial barrier function in a large vessel.

Murine Aortic Crush Injury: An Efficient In Vivo Model of Smooth Muscle Cell Proliferation and Endothelial Function

Restenosis following cardiovascular procedures (bypass surgery, angioplasty, or stenting) is a significant problem reducing the durability of these procedures. An ideal therapy would inhibit smooth muscle cell (VSMC) proliferation while promoting regeneration of the endothelium. We describe a model for simultaneous assessment of VSMC proliferation and endothelial function in vivo.

小鼠主动脉夹层损伤:高效<em&gt;体内</em&gt;平滑肌细胞增殖和内皮功能模型

Arterial reconstruction, whether angioplasty or bypass surgery, involves iatrogenic trauma causing endothelial disruption and vascular smooth muscle cell ...

大鼠颈动脉球囊损伤模型试验抗血管重建治疗

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小鼠加速动脉硬化的诱导:"电线损伤"模型

重复性的动脉剥脱损伤腹主动脉阻断在小鼠模型

家兔加速动脉粥样硬化模型的研究--髂动脉球囊损伤的方法学观察

大鼠胡萝卜动脉压力控制段气球损伤与腹腔ventit 治疗应用

小鼠主动脉夹层损伤:高效

大鼠颈动脉球囊损伤模型试验抗血管重建治疗

摘要

探索更多视频

此视频中的章节

一个型号的不安流致动脉粥样硬化小鼠颈动脉部分结扎术和颈动脉内皮细胞的RNA分离的简单方法

小鼠Spinotrapezius模型来评估的影响小动脉结扎​​术，微血管功能与重塑

颈动脉支架植入再狭窄的研究的小鼠模型

血管球囊损伤和腔内管理在大鼠颈动脉

股动脉线损伤的小鼠模型的血管周围给药补丁植入

小鼠加速动脉硬化的诱导:"电线损伤"模型

重复性的动脉剥脱损伤腹主动脉阻断在小鼠模型

家兔加速动脉粥样硬化模型的研究--髂动脉球囊损伤的方法学观察

大鼠胡萝卜动脉压力控制段气球损伤与腹腔ventit 治疗应用

小鼠主动脉夹层损伤:高效

小鼠Spinotrapezius模型来评估的影响小动脉结扎术，微血管功能与重塑