We are grateful to Dr. Clowes for first developing and describing this method. We are also thankful to Dr. Tulis for his detailed protocol which has been fundamentally helpful to our previous, current and future work. This work was supported by grants R01HL097111 and R01HL123364 from the NIH to M.T., and by American Heart Association grant 14GRNT18880008 to M.T.
We would like to thank Rachel Newton for her expert technical support and for her valuable help during the filming process.

注：以下の実験のための動物の使用を見直し、施設内動物管理使用委員会（IACUC）によって承認されています。 1.術前手続き<ol style="margin-left: 40px;"><li>使用前に手術器具を滅菌する。 <ol><li>すべての手術器具を手術前24時間以下オートクレーブ。複数の手術が同日に行われている場合は、手術の間の乾燥ビーズ滅菌器によって楽器を殺菌。 </li></ol></li><li>フィルター滅菌し、使用前に生理食塩水を。 </li><li>ラットを秤量し、麻酔薬（ケタミン80 mg / kgをとキシラジン7 mg / kgを）の投与量を計算する。 </li><li>腹腔内（IP）麻酔薬を管理します。 <ol><li> 5〜10分で足指のピンチによる鎮静の妥当性を確認してください。鎮静が完了していない場合は、薬（ケタミン7ミリグラム/ kgおよびキシラジンは0.6mg / kg）を追加の小さな用量を投与。 </li><li>針が配信薬、イントラあたりに十分な深さであることを確認してくださいitoneally腹腔内に全体の薬液を提供する失敗は不十分な鎮静の原因になりますので。 注：注射部位の皮膚の潰瘍及び脱毛は、数日手術後不注意皮下（sc）薬液注入による表示されます。 </li></ol></li><li> 3ミリリットルの無菌食塩水を皮下（s。c。）注射する。滅菌綿棒を用いて、乾燥から角膜を防ぐために、両眼に眼軟膏を少量適用する。 </li><li>加熱装置を準備します。マイクロ波または水浴によって事前温熱パッド。 </li><li>外科プラットフォーム上で仰向け動物を置く。 <ol><li>腹側頸部領域で毛を削除します。 30秒待ってからガーゼで完全に拭き取って、綿棒で毛リムーバーを適用します。 </li><li>ポビドンヨードスクラブと70％エタノールで首を綿棒。 </li></ol></li><li>ガウン、ヘアカバー、外科マスク、眼鏡を含め、個人保護具を使用すること。 STERに置く無菌手術器具や消耗品を取り扱う前に最後に手術用手袋をILE。 </li><li>暴露だけ首領域との無菌手術用シートでラットをドレープ。 </li></ol> 2.外科的処置<ol style="margin-left: 40px;"><li>外科手術中に、15分毎でつま先のピンチによって、動物の鎮静深度を確認してください。動物はつま先のピンチに応答する場合、ケタミンとキシラジンの追加の小さな用量（初期投与量の10％）を追加します。 </li><li>左総頚動脈（CCA）を解剖<ol><li>首の真ん中にまっすぐ縦切開を作るためにメスを使用してください。皮膚切開のおおよその長さは、動脈1.5-2センチ部分を単離する目的のために1.5〜2センチ。長さは変更される場合があります研究の目的に依存します。 </li><li>露骨に皮膚から結合組織を解剖。鉗子のヒントを維持し、皮膚やその下の組織を穿刺しないように注意してください。 </li><li>長手方向にalon筋肉層を分析グラム気管の左側。 </li><li>筋層を開放すると、密着迷走神経と左CCAを視覚化する。ぶっきらぼうにストレッチ最小限に迷走神経を分離するために細心の注意を払って左頸動脈と一緒に解剖する。 </li><li>分岐点まで遠位にCCAを解剖。内頸動脈（ICA）と外頚動脈（ECA） - 慎重に分岐し、2つのブランチ解剖。 </li><li>動脈1.5-2センチ約部分が周囲の組織から分離されるまで、CCAの周りに解剖してください。 </li></ol></li><li>バルーン障害<ol><li>恒久的には約5ミリメートル離れて分岐からECA上の合字を作る。永久にECAとICAの分岐に近いECAの後頭部枝を連結。どんな場合にも恒久的に分岐し、ECAの合字の間場所、他の枝を結紮 - 例えば、上甲状腺ブランチを。すべての合字のために使用される縫合糸は4-0黒ですシルク。 CCAの近位端とICAの先端にクリップ。 注：ここで、血流が（CCAとICAに）クリッピングのいずれかを介して恒久的に（ECA上の）ライゲーションを介して、または一時的に停止されました。分岐部領域内の管腔内容物は、全身循環から単離されている。 </li><li>小マイクロはさみによってECA上の動脈切開切開を行います。切開は、遠位縫合糸の結び目の近くにあることを確認してください。生理食塩水と綿棒で清掃して血。 </li><li> ECA内腔に膨張していない2Fバルーンカテーテルを挿入します。 CCA内腔の近位にバルーンカテーテルを進める。クリップは留まるところ、その先端が到達するまで、近位にカテーテルを前進してください。 </li><li> 3方活栓のメスルアーロックにバルーン膨張デバイスを接続し、バルーンカテーテルに3方活栓の雄ルアーロックを接続します。 </li><li>徐々に直径の1.5倍に頸動脈を拡張させるために、約1.5気圧の圧力でバルーンを膨張させる。 </lI&gt; <li>ゆっくりと回転戻って分岐部にバルーンを引っ張る。 </li><li>バルーンを収縮し、近位端に戻ってそれを進める。再びそれを膨らませると引き戻し手順をさらに2回繰り返します。 </li><li>動脈内腔からバルーンカテーテルを引き出す。 </li></ol></li><li>試薬の管腔内投与（ 例えば、siRNAは、薬） 注記：ここでは、使用される試薬のいずれかをコードするのshRNAは、間質相互作用分子1（STIM1）または非標的shRNAを制御ターゲッティングレンチウイルス粒子を含有する溶液であった。 STIM1は、原形質膜のCa 2+チャネルの活性化を制御するERのCa 2+センサであり、増殖、遊走表現型12,30-33に血管平滑筋分化の間にアップレギュレートされる単一の膜貫通小胞体（ER）タンパク質である。 <ol><li>注射器（24 G 1.6センチ）に血管内オーバーザニードルカテーテルを取り付けます。テストREAGの吸引除去30μlのソリューションエント。 ECAの同じ切開にカテーテルを挿入します。 </li><li> CCAにカテーテル先端を進め、カテーテルを固定し、一時的に切開を閉じるためにECA上の単一結び目と縫合糸の部分を結ぶ。 </li><li> CCAの内腔に検査試薬溶液を注入する。 30分間の血管内腔内の溶液にしてください。生理食塩水で湿った露出した組織を維持し、湿ったガーゼでそれをカバーしています。 </li><li>インキュベーション後、残りの溶液を吸引する。その単一の結び目を緩め、カテーテルを撤回。 </li><li>動脈切開切開に対して近位縫合糸の切れ端でECAを結ぶ。分岐部にできるだけ近い結び目を作る。 </li></ol></li><li>傷をクローズアップ。 <ol><li>バルーン傷害とカテーテル導入は、血管の漏れやパンクの原因となりますので、ICA上のクリップを削除し、すべての漏れがあるかどうかを確認します。出血が観察される場合、ガーゼを適用し、出血を止めるために穏やかな圧力を加える。 </li><li>削除するCCA上の他のクリップ。 </li><li>出血の兆候がないことを確認し、すべてのクランプや他の手術器具を取り外します。余分な縫合糸を切り取ります。 </li><li>閉じる傷用いた皮膚縫合糸（4-0黒絹）。 Povidon-ヨウ素または他の抗敗血症性/殺菌/殺ウイルス剤を用いて、閉じた傷口のすべての側面に綿棒。滅菌生理食塩水の皮下を3mlを注入する</li></ol></li></ol> 3.術後の手順<ol style="margin-left: 40px;"><li>手術後の熱パッドの上にラットを保管してください。ラットに筋肉内注射（IM）を介して0.05​​ mg / kgをブプレノルフィンの1用量を投与。復旧手順の間、湿った動物の目と口を保つ。それは目を覚ましや通院になるまで動物を監視します。 </li><li>それが完全に回復するまで、すべての寝具なしできれいなケージに動物を置きます。回復後、動物を動物室に戻し、個別に収容される。 </li></ol>

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M., 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=Knockout+rats+via+embryo+microinjection+of+zinc-finger+nucleases.">Knockout rats via embryo microinjection of zinc-finger nucleases.</a> Science. 325, 433 (2009).</li><li>Tesson, L., 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=Knockout+rats+generated+by+embryo+microinjection+of+TALENs.">Knockout rats generated by embryo microinjection of TALENs.</a> Nature Biotechnology. 29, 695-696 (2011).</li><li>Li, D., 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=Heritable+gene+targeting+in+the+mouse+and+rat+using+a+CRISPR-Cas+system.">Heritable gene targeting in the mouse and rat using a CRISPR-Cas system.</a> Nature Biotechnology. 31, 681-683 (2013).</li><li>Potier, M., 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=Evidence+for+STIM1-+and+Orai1-dependent+store-operated+calcium+influx+through+ICRAC+in+vascular+smooth+muscle+cells:+role+in+proliferation+and+migration.">Evidence for STIM1- and Orai1-dependent store-operated calcium influx through ICRAC in vascular smooth muscle cells: role in proliferation and migration.</a> FASEB Journal : Official Publication Of The Federation Of American Societies For Experimental Biology. 23, 2425-2437 (2009).</li><li>Aubart, F. C., 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=RNA+interference+targeting+STIM1+suppresses+vascular+smooth+muscle+cell+proliferation+and+neointima+formation+in+the+rat.+Molecular+Therapy.">RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat. Molecular Therapy.</a> The Journal Of The American Society Of Gene Therapy. 17, 455-462 (2009).</li><li>Berra-Romani, R., Mazzocco-Spezzia, A., Pulina, M. V., Golovina, V. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ca2++handling+is+altered+when+arterial+myocytes+progress+from+a+contractile+to+a+proliferative+phenotype+in+culture.+American+journal+of+physiology.">Ca2+ handling is altered when arterial myocytes progress from a contractile to a proliferative phenotype in culture. American journal of physiology.</a> Cell Physiology. 295, C779-C790 (2008).</li><li>Bisaillon, J. M., 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=Essential+role+for+STIM1/Orai1-mediated+calcium+influx+in+PDGF-induced+smooth+muscle+migration.+American+journal+of+physiology.">Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration. American journal of physiology.</a> Cell Physiology. 298, C993-C1005 (2010).</li><li>Tulis, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rat+carotid+artery+balloon+injury+model.">Rat carotid artery balloon injury model.</a> Methods In Molecular Medicine. 139, 1-30 (2007).</li><li>Zhang, W., Trebak, M., Szallasi, A., B&#237;r&#243;, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Balloon+Injury+in+Rats+as+a+Model+for+Studying+TRP+Channel+Contribution+to+Vascular+Smooth+Muscle+Remodeling.">Balloon Injury in Rats as a Model for Studying TRP Channel Contribution to Vascular Smooth Muscle Remodeling.</a> T TRP Channels in Drug DiscoveryMethods in Pharmacology and Toxicology. , 101-111 (2012).</li><li>Tulis, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Histological+and+morphometric+analyses+for+rat+carotid+balloon+injury+model).">Histological and morphometric analyses for rat carotid balloon injury model).</a> Methods In Molecular Medicine. 139, 31-66 (2007).</li></ol>

The authors declare that they have no competing financial interests.

ラット頸動脈バルーン損傷はよく2007 34 Tulisによって記載されている。それは、包括的に博士Tulisこの手順のすべての詳細を説明してきた。この手順を実行するに興味がある読者は非常にTulis &#39;プロトコルを読むことをお勧めします。しかし、我々は博士Tulisに同意していない一つのことがあります：代わりに生理食塩水または液体のいずれかの種類でバルーンを膨張させるのが、私たちは空気でそ?...

バルーンカテーテルは、血管内のアテロームまたは血栓閉塞部位を広げる目的で、血管形成術の手順で使用する医療機器である。狭め血管内腔は、膨張バルーンによって開くように強制され、血液供給は、狭心症、心筋梗塞、および下肢痛のような下流の虚血症状を緩和するために連続的に復元される。それにもかかわらず、血管形成術の大成功は、そのような血管内腔（再狭窄）1の再狭小血管気圧外傷（バルーン損傷）、すなわち血管壁リモデリングを引き起こす力の結果として、多くの場合、術後の合併症によって減少されました。 多くの動物モデルは、研究者は、バルーン損傷に関連する血管壁リモデリング2のメカニズムを理解するための血管形成術を模倣開発されてきた。モデリングのために利用されるすべての動物種の中では、ラットは、最も頻繁にものを用いられる。 ℃ウサギ、イヌおよびブタにompared、ラットの利点は、その低コスト、使用が比較的容易とラットの生理学の現在の知識である。マウスは、遺伝子操作株の広い範囲で追加の利点を有するが、マウスの血管は、バルーンカテーテルを挿入するには小さすぎる。過去30年間にわたり、実験ラットは、研究者が3-6を改造新生内膜形成と血管を支える分子·細胞メカニズムのより良い理解を得ることができました。バルーン傷害を越え、血管リモデリングはまた、アテローム性動脈硬化症7,8、高血圧9、及び動脈瘤10などのほとんどの主要な血管疾患に関与している。このように、知識は、バルーン傷害モデルを通して得、一般に、全体的な血管壁の疾患の研究に有益である。 ラットバルーン傷害モデルの全体的な目標は、だけでなく、さらに血管疾患を理解するだけでなく、のための新規薬剤の効力を試験することである疾病コントロール11,12。再狭窄の現在の臨床薬物治療は、右血管形成術後の血管内腔を介して配置された薬剤溶出ステントにより適用される。動物モデルでは、新しいエージェント·テストのための効率がさらに経済的な方法は十分に開発されたローカル腔内灌流法である。候補このメソッドを使ってテストされている薬剤の小分子薬を含んで13,14、サイトカインまたは成長は15,16因子 、薬剤を操作する遺伝子（cDNAクローンは、siRNA など ） を 17-20、及び新規な医薬製剤21,22。 これまでに、ラットバルーン傷害モデルは、血管疾患/障害を研究するための最も有用なモデルの一つである。それは、最初のステップは、in vivoでのin vitroでの移動は、通常のように、ベンチからベッドサイドへの基本的なステップですが、それは最後の1であってはならない。ラットの実験の結果は、審議し、さらに人間への変換の前に特徴付けされる必要があるによる血管床および血管の解剖学的構造ならびにヒトおよびラットの23〜26との間の本質的な種差の差に臨床使用。それにもかかわらず、それはまだ翻訳医学研究に不可欠なツールである。このような研究は、遺伝的に改変されたラットの欠如によって制限されるために使用されるが、このようなジンクフィンガーとしての新規なゲノムアプローチは29ノックアウトラットを簡単にアクセスできるようにしている、27ヌクレアーゼTALENs 28およびCRISPR-Casのため、それはもはや問題ではなかった。

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	<tbody>
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			<td height="21" style="height:21px;width:384px;">Name of Material/ Equipment</td>
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			<td height="21" style="height:21px;">Fogarty balloon embolectomy catheters, 2 French&#160;</td>
			<td>Edwards Lifesciences, Germany</td>
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			<td height="21" style="height:21px;">Deltaphase Operating Board - Includes 2 Pads &#38; 2 Insulators</td>
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			<td height="21" style="height:21px;">Hartmann Mosquito Forceps 4&#8221; curved</td>
			<td>Apiary Medical, Inc. San Diego, CA</td>
			<td>gS 22.1670</td>
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			<td height="21" style="height:21px;">Crile Retractor 4&#8221; double ended</td>
			<td>Apiary Medical, Inc.</td>
			<td>gS 34.1934</td>
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			<td height="21" style="height:21px;">Other surgical instruments</td>
			<td>Roboz Surgical Instrument Company, Inc., Gaithersburg, MD</td>
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			<td height="21" style="height:21px;">Peripheral Intravenous (I.V.) Cannula, 24G</td>
			<td>BD</td>
			<td>381312</td>
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			<td height="21" style="height:21px;">Ketamine HCl, 100mg/mL, 10mL</td>
			<td>Ketaset- Patterson Vet</td>
			<td>07-803-6637&#160;</td>
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			<td>Ketaset- Patterson Vet</td>
			<td>07-850-2280</td>
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			<td height="21" style="height:21px;">Nair Baby Oil Hair Removal Lotion-9 oz</td>
			<td>Amazon/Walmart/CVS</td>
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			<td height="21" style="height:21px;">Inflation Device</td>
			<td>Demax Medical</td>
			<td>DID30</td>
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			<td height="21" style="height:21px;">D300 3-way Stopcock</td>
			<td>B.Braun Medical Inc.</td>
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			<td height="21" style="height:21px;">Artificial Tears Ointment&#160;</td>
			<td>Rugby Laboratories, Duluth, GA</td>
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</table>

vascular balloon injury and intraluminal administration in rat carotid artery

ラットでの頸動脈バルーン傷害モデルは、よく20年以上のために確立されている。それは、血管平滑筋分化、新生内膜形成および血管リモデリングに関与する分子や細胞メカニズムを研究するための重要な方法のまま。雄Sprague-Dawleyラットをこのモデルのために最も頻繁に用いられる動物である。女性ホルモンは血管疾患に対して保護的であり、したがって、このプロシージャにバリエーションを導入として雌ラットは好ましくない。左頸動脈は、一般的に、陰性対照として右の頸動脈に怪我をされている。左頸動損傷は、内皮をdenudesとs血管壁を膨張させる膨張したバルーンによって引き起こされる。損傷後、そのような薬理学的化合物および遺伝子またはshRNA転送のいずれかの使用のような潜在的な治療戦略を評価することができる。典型的には遺伝子またはshRNA転送のため、血管内腔の負傷した部分が局所的にvで30分間形質導入され損傷した血管壁の送達および発現のためのタンパク質またはshRNAのいずれかをコードするIRAL粒子。増殖性血管平滑筋細胞を表す新生内膜肥厚は、通常、損傷後2週間でピーク。容器は、主に細胞および分子細胞シグナル伝達経路の解析、並びに遺伝子及びタンパク質発現のために、この時点で収穫される。容器はまた、意図された実験の目的に応じて、特定のタンパク質または経路の発現及び/又は活性化の開始を決定するために、以前の時点で収穫することができる。容器は、組織学的染色、免疫組織化学、タンパク質/ mRNAのアッセイ、および活性アッセイを用いて特徴付けし、評価することができる。同じ動物からの無傷の右頸動脈は理想内部対照である。分子および細胞パラメータにおける傷害誘導変化は、内部右側対照動脈に損傷動脈を比較することによって評価することができる。同様に、治療法は傷を負う比較することによって評価することができますコントロールにDと治療動脈は唯一の動脈を負傷した。

二週間損傷後、頸動脈を採取し、切片化し、形態学的分析に付す。動脈は、クロス切断し、H＆Eで染色している（ 図1、図2B、Cおよび3）。ラット頸動脈の壁はピンク色の線として表示され弾性板の4層が含まれています。最外部薄層、外弾性板（EEL）と最も内側の薄層、内弾性板（IEL）の間の領域は、メディア平滑筋層（ 図1）である。 IELの内側の面積は内膜、無傷の...

Watch this Scientific Journal Video about Vascular Balloon Injury and Intraluminal Administration in Rat Carotid Artery at JoVE.com

Vascular Balloon Injury and Intraluminal Administration in Rat Carotid Artery

このプロトコルは、ラット頚動脈上の管腔内損傷を引き起こすと今後新生内膜過形成を誘発するためにバルーンカテーテルを使用しています。これは、傷害に応答する脈管リモデリングのメカニズムを研究するための十分に確立されたモデルである。また、広く、潜在的な治療的アプローチの有効性を決定するために使用される。

ラット頸動脈における血管バルーン傷害と管腔内投与

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 ...

vascular-balloon-injury-intraluminal-administration-rat-carotid

Research

JoVE Journal

Medicine

16.2K ビュー.  State University of New York College of Nanoscale Science and Engineering (SUNY CNSE). このプロトコルは、ラット頚動脈上の管腔内損傷を引き起こすと今後新生内膜過形成を誘発するためにバルーンカテーテルを使用しています。これは、傷害に応答する脈管リモデリングのメカニズムを研究するための十分に確立されたモデルである。また、広く、潜在的な治療的アプローチの有効性を決定するために使用される。 

ビデオ: Vascular Balloon Injury and Intraluminal Administration in Rat Carotid Artery

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

Neointimal hyperplasia is one the primary causes of stenosis in arterialized veins that are of great importance in arterial coronary bypass surgery, in peripheral arterial bypass surgery as well as in arteriovenous fistulas.1-5 The experimental procedure of vein graft interposition in the common carotid artery by using the cuff-technique has been applied in several research projects to examine the aetiology of neointimal hyperplasia and therapeutic options to address it. 6-8 The cuff prevents vessel anastomotic remodeling and induces turbulence within the graft and thereby the development of neointimal hyperplasia.
Using the superior caval vein graft is an established small-animal model for venous arterialization experiment.9-11 This current protocol refers to an established jugular vein graft interposition technique first described by Zou et al., 9 as well as others.12-14 Nevertheless, these cited small animal protocols are complicated.
To simplify the procedure and to minimize the number of experimental animals needed, a detailed operation protocol by video training is presented. This video should help the novice surgeon to learn both the cuff-technique and the vein graft interposition. Hereby, the right external jugular vein was grafted in cuff-technique in the common carotid artery of 21 female Sprague Dawley rats categorized in three equal groups that were sacrificed on day 21, 42 and 84, respectively. Notably, no donor animals were needed, because auto-transplantations were performed. The survival rate was 100 % at the time point of sacrifice. In addition, the graft patency rate was 60 % for the first 10 operated animals and 82 % for the remaining 11 animals. The blood flow at the time of sacrifice was 8&plusmn;3 ml/min. In conclusion, this surgical protocol considerably simplifies, optimizes and standardizes this complicated procedure. It gives novice surgeons easy, step-by-step instruction, explaining possible pitfalls, thereby helping them to gain expertise fast and avoid useless sacrifice of experimental animals.

Neointimal hyperplasia is the primary cause of stenosis in arterialized veins. We propose a new protocol whereby the right external jugular vein is grafted using the cuff technique in the common carotid artery of Sprague Dawley rats. The survival rate was 100 % at the time point of sacrifice.

ラットの総頚動脈で外頚静脈グラフトの介在：洗練された顕微鏡下手術の訓練

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

医学

Optimized System for Cerebral Perfusion Monitoring in the Rat Stroke Model of Intraluminal Middle Cerebral Artery Occlusion

The translational potential of pre-clinical stroke research depends on the accuracy of experimental modeling. Cerebral perfusion monitoring in animal models of acute ischemic stroke allows to confirm successful arterial occlusion and exclude subarachnoid hemorrhage. Cerebral perfusion monitoring can also be used to study intracranial collateral circulation, which is emerging as a powerful determinant of stroke outcome and a possible therapeutic target. Despite a recognized role of Laser Doppler perfusion monitoring as part of the current guidelines for experimental cerebral ischemia, a number of technical difficulties exist that limit its widespread use. One of the major issues is obtaining a secure and prolonged attachment of a deep-penetration Laser Doppler probe to the animal skull. In this video, we show our optimized system for cerebral perfusion monitoring during transient middle cerebral artery occlusion by intraluminal filament in the rat. We developed in-house a simple method to obtain a custom made holder for twin-fibre (deep-penetration) Laser Doppler probes, which allow multi-site monitoring if needed. A continuous and prolonged monitoring of cerebral perfusion could easily be obtained over the intact skull.

Cerebral perfusion monitoring has been demonstrated to improve accuracy in ischemic stroke models. Technical difficulties often limit the use of this essential tool for cerebrovascular research. In this video, an optimized system is shown to obtain a single or multi-site hemodynamic monitoring during intraluminal middle cerebral artery occlusion in rats.

腔内中大脳動脈閉塞のラット脳卒中モデルにおける脳血流モニタリングのための最適化されたシステム

The translational potential of pre-clinical stroke research depends on the accuracy of experimental modeling. Cerebral perfusion monitoring in animal ...

Catheterization of the Carotid Artery and Jugular Vein to Perform Hemodynamic Measures, Infusions and Blood Sampling in a Conscious Rat Model

The success of a small animal model to study critical illness is, in part, dependent on the ability of the model to simulate the human condition. Intra-tracheal inoculation of a known amount of bacteria has been successfully used to reproduce the pathogenesis of pneumonia which then develops into sepsis. Monitoring hemodynamic parameters and providing standard clinical treatment including infusion of antibiotics, fluids and drugs to maintain blood pressure is critical to simulate routine supportive care in this model but to do so requires both arterial and venous vascular access. The video details the surgical technique for implanting carotid artery and common jugular vein catheters in an anesthetized rat. Following a 72 hr recovery period, the animals will be re-anesthetized and connected to a tether and swivel setup attached to the rodent housing which connects the implanted catheters to the hemodynamic monitoring system. This setup allows free movement of the rat during the study while continuously monitoring pressures, infusing fluids and drugs (antibiotics, vasopressors) and performing blood sampling.

Vascular accesses to measure hemodynamics, provide fluids and perform blood sampling are important to any small animal model study. We present a technique for implanting catheters into the carotid artery and the common jugular vein in an anesthetized rat for connecting to a system to perform monitoring, infusions and sampling.

配慮ラットモデルにおける血行動態の措置、煎茶や血液サンプリングを実行するために頸動脈と頸静脈のカテーテル

The success of a small animal model to study critical illness is, in part, dependent on the ability of the model to simulate the human condition. ...

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study model. As the use of mouse models are often a vital step in preclinical drug discovery and drug development1-8, it is necessary to design a system to introduce drugs into mice in a uniform, reproducible manner. Ideally, the system should permit the collection of blood samples at regular intervals over a set time course. The ability to measure drug concentrations by mass-spectrometry, has allowed investigators to follow the changes in plasma drug levels over time in individual mice1, 9, 10. In this study, paclitaxel was introduced into transgenic mice as a continuous arterial infusion over three hours, while blood samples were simultaneously taken by retro-orbital bleeds at set time points. Carotid artery infusions are a potential alternative to jugular vein infusions, when factors such as mammary tumors or other obstructions make jugular infusions impractical. Using this technique, paclitaxel concentrations in plasma and tissue achieved similar levels as compared to jugular infusion. In this tutorial, we will demonstrate how to successfully catheterize the carotid artery by preparing an optimized catheter for the individual mouse model, then show how to insert and secure the catheter into the mouse carotid artery, thread the end of the catheter out through the back of the mouse&#8217;s neck, and hook the mouse to a pump to deliver a controlled rate of drug influx. Multiple low volume retro-orbital bleeds allow for analysis of plasma drug concentrations over time.

This method was developed with the goal of delivering a steady drug solution via the carotid artery, to assess the pharmacokinetics of novel drugs in mouse models.

マウスにおけるタキサンの薬物動態学的および薬力学的分析のための頸動脈煎茶

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study ...

Ferric Chloride-induced Thrombosis Mouse Model on Carotid Artery and Mesentery Vessel

Severe thrombosis and its ischemic consequences such as myocardial infarction, pulmonary embolism and stroke are major worldwide health issues. The ferric chloride injury is now a well-established technique to rapidly and accurately induce the formation of thrombi in exposed veins or artery of small and large diameter. This model has played a key role in the study of the pathophysiology of thrombosis, in the discovery and validation of novel antithrombotic drugs and in the understanding of the mechanism of action of these new agents. Here, the implementation of this technique on a mesenteric vessel and carotid artery in mice is presented. The method describes how to label circulating leukocytes and platelets with a fluorescent dye and to observe, by intravital microscopy on the exposed mesentery, their accumulation at the injured vessel wall which leads to the formation of a thrombus. On the carotid artery, the occlusion caused by the clot formation is measured by monitoring the blood flow with a Doppler probe.

The FeCl3 induced thrombosis model in mice is described herein. A method to monitor thrombus growth by intravital microscopy observation on a mesenteric vessel and by blood flow measurement in the carotid artery is presented.

塩化第二鉄誘発性頚動脈および腸間膜血管に血栓症のマウスモデル

Severe thrombosis and its ischemic consequences such as myocardial infarction, pulmonary embolism and stroke are major worldwide health issues. The ferric ...

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.

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.

ラット頸動脈バルーン損傷モデルは、抗血管リモデリングの治療薬をテストします

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 ...

Intraluminal Drug Delivery to the Mouse Arteriovenous Fistula Endothelium

Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The simple murine AVF model was combined with intraluminal administration of drug solution to the venous endothelium at the same time as fistula creation. Technical aspects of this model are discussed. Under general anesthesia, an abdominal incision is made and the aorta and inferior vena cava (IVC) are exposed. The infra-renal aorta and IVC are dissected for clamping. After proximal and distal clamping, the puncture site is exposed and a 25 G needle is used to puncture both walls of the aorta and into the IVC. Immediately after the puncture, a reporter gene-expressing viral vector was infused in the IVC via the same needle, followed by 15 min of incubation. The intraluminal administration method enabled more robust viral gene delivery to the venous endothelium compared to administration by the external route. This novel method of delivery will facilitate studies that explore the role of the endothelium in AVF maturation and enable intraluminal drug delivery at the time of surgical operation.

After puncturing the aorta through the inferior vena cava (IVC) to create an aorto-caval fistula in the mouse, solution containing a drug is infused into the IVC via the same needle, followed by incubation. This method enables more robust drug delivery to the venous endothelium compared to the external route.

マウスの動静脈瘻内皮への管腔内薬物送達

Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The ...

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.

加速動脈硬化家兎モデル: 内腸骨動脈バルーン傷害の方法論的視点

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

Phase Contrast Magnetic Resonance Imaging in the Rat Common Carotid Artery

Phase contrast magnetic resonance imaging (PC-MRI) is a noninvasive approach that can quantify flow-related parameters such as blood flow. Previous studies have shown that abnormal blood flow may be associated with systemic vascular risk. Thus, PC-MRI can facilitate the translation of data obtained from animal models of cardiovascular diseases to pertinent clinical investigations. In this report, we describe the procedure for measuring blood flow in the common carotid artery (CCA) of rats using cine-gated PC-MRI and discuss relevant analysis methods. This procedure can be performed in a live, anesthetized animal and does not require euthanasia after the procedure. The proposed scanning parameters yield repeatable measurements for blood flow, indicating excellent reproducibility of the results. The PC-MRI procedure described in this article can be used for pharmacological testing, pathophysiological assessment, and cerebral hemodynamics evaluation.

The overall goal of this procedure is to measure the blood flow in the rat common carotid artery by using noninvasive phase contrast magnetic resonance imaging.

ラットの総頸動脈で位相コントラスト磁気共鳴イメージング

Phase contrast magnetic resonance imaging (PC-MRI) is a noninvasive approach that can quantify flow-related parameters such as blood flow. Previous ...

Ferric Chloride-induced Canine Carotid Artery Thrombosis: A Large Animal Model of Vascular Injury

Occlusive arterial thrombosis leading to cerebral ischemic stroke and myocardial infarction contributes to ~13 million deaths every year globally. Here, we have translated a vascular injury model from a small animal into a large animal (canine), with slight modifications that can be used for pre-clinical screening of prophylactic and thrombolytic agents. In addition to the surgical methods, the modified protocol describes the step-by-step methods to assess carotid artery canalization by angiography, detailed instructions to process both the brain and carotid artery for histological analysis to verify carotid canalization and cerebral hemorrhage, and specific parameters to complete an assessment of downstream thromboembolic events by utilizing magnetic resonance imaging (MRI). In addition, specific procedural changes from the previously well-established small animal model necessary to translate into a large animal (canine) vascular injury are discussed.

Here, we present the modifications necessary to a well characterized and commonly used small animal ferric chloride-induced (FeCl3) carotid artery injury model for use in a large animal vascular injury model. The resulting model can be utilized for pre-clinical trial assessment of both prophylactic and thrombolytic pharmacological and mechanical interventions.

塩化第二鉄によるイヌ総頚動脈血栓症: 血管損傷の大動物モデル

Occlusive arterial thrombosis leading to cerebral ischemic stroke and myocardial infarction contributes to ~13 million deaths every year globally. Here, ...