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.

참고 : 쥐 풍선 손상 모델과 재조합 sRAGE 초음파 초음파 연구의 주입을 포함하여 관련 절차의 사용은 노화에 국립 연구소의 동물 관리 및 사용위원회 (ACUC), NIH에 의해 승인되었습니다. 1. 사전 수술 준비 <ol><li> 악기, 외과 플랫폼 및 개인 보호 장비. <ol><li> 이 절차에 사용 된 모든 수술기구 및 시약에 대한 재료 및 장비의 표를 참조하십시오. 수술하기 전에 모든 수술 도구를 압력솥. 참고 : 같은 날에 실시 여러 수술의 경우, 수술 사이에 악기를 소독하기 위해 미리 가열 된 유리 구슬 살균기를 사용합니다. </li><li> 70 % 알코올로 운영 플랫폼의 표면을 소독. 수술 가운, 헤어 커버, 수술 용 마스크, 보호 안경, 장갑 착용. 추가 우리를 위해 수술 플랫폼 근처에 멸균 장갑의 상자를 남겨이자형. </li></ol></li><li> 풍선 카테터의 준비. <ol><li> 멸균 물 1 ML의 주사기를 입력하고 멸균 물이 채워진 두 방향 스톱 콕에 주사기를 연결합니다. 부드럽게 풍선 카테터의 루어 잠금 부를 작성하고, 카테터의 개구부로부터 공기 방울을 제거하기 위해 꼭지를 통해 물을 밀어. </li><li> 풍선을 보장하기 위해 테스트 풍선 인플레이션 물 0.02 ml로 팽창 할 수 있습니다. 탈수 및 오염을 방지하기 위하여 수술 전 멸균 용기에 풍선의 끝 부분을 저장한다. </li></ol></li><li> 마취 및 동물 준비. <ol><li> 남성의 Wistar 쥐 무게 (4백-4백50그램)과 ID를 확인하기 위해 귀 태그를 확인합니다. 예를 들면 발가락이나 꼬리를 곤란으로 페달 철수 반사를 확인하여 진정 작용의 깊이를 확인 후, 유도 챔버에서 쥐를 놓습니다 기화기를 켜고 3.5-4.0 %로 이소 플루 란 레벨 1.5-2.0 L.에 산소 레벨을 조정 동물의. </li><li> (마취에 도달 한 후 <em&gt; 동물) 페달 움츠림 반사 결여 즉, 외과 용 플랫폼으로 전송하고, 동물을 마취 기화기에 연결하는 노즈 콘 래트 후크. L.는 주기적으로 쥐가 완전히 편안하고 움직이지 않는 것을 보장하기 위해 동물의 발가락이나 꼬리를 곤란에 의해 진정의 깊이를 확인 0.6-1.0에 1.5-2.0와 산소로 이소 플루 란 농도를 조정합니다. </li><li> 마취의 수술 수준에 도달 한 후, 바로 동물 머리를 가위로 흉골 위 아래 턱에서 복부 목 부위를 면도하고 포비돈 - 요오드 및 70 % 에탄올 3 회 1:10 희석을 교대로 면도 피부를 닦아. </li><li> 건조되는 것을 방지하기 위해 면봉으로 동물의 개방 눈 안과 솔루션을 놓습니다. 동작 중에 건조를 방지하기 위해 물을 마시는 동물의 혀와 입 적셔. </li><li> 멸균 된 수술 용 시트 래트 커버와 목 부위를 노출 낱장. 앙와위 오의 동물을 배치NA는 의사를 향해 머리 수술 플랫폼에 패드를 가열. 테이프를 사용하여 수술 플랫폼 동물의 사지를 고정. </li></ol></li></ol> 2. 외과 적 치료 <ol><li> 해부과 왼쪽 경동맥의 분리 <ol><li> 모든 방법을 바로 흉곽 위의 흉골의 상단에 꼬리를 향해 한 방향으로 턱 아래 직선 절개를 만들기 위해 메스를 사용합니다. 퉁명스럽게 근육 층을 노출 피부 아래 침 샘 조직을 해부하는 7S 집게를 사용합니다. 별도 근육 조직 경동맥 혈관 목 영역에있는 미주 신경에 액세스한다. </li><li> 퉁명스럽게 경동맥을 주변 조직을 해부, 조심스럽게 미주 신경 및 혈관 근막이 손상을 방지하기 위해 분리. 계속 흉골 아래로 내부 및 외부 가지와 경동맥을 노출 경동맥 분기점까지 해부. </li></ol></li><li> Arteriot의 준비OMY <ol><li> 수축과 지혈를 들어, 왼쪽 경동맥에서 가장 근위 사이트에서 합자 및 분기점에 위치 즉시 말단에서 또 다른 합자를 배치합니다. </li><li> 헤드쪽으로 동맥 후퇴 최대한 분기점으로부터 외부 경동맥에서 4.0 실크 봉합사를 배치했다. 영구 상행 인두, 후두 및 혈관 누출을 방지하기 위해 우수한 갑상선 포함한 외부 경동맥 따라 4.0 실크 봉합사를 이용하여 작은 동맥 결찰. </li><li> 중요한 역행 혈액 손실을 방지하기 위해 내부 경동맥 주위에 4.0 실크 봉합사를 놓습니다. 일반적으로, 내부 지점의 가용 길이는 최소화된다. 내부 경동맥을 시각화하기 위해 부드럽게 오른쪽 위에 놓인 경동맥의 동맥을 수축하여 가능한 한 많은 내부 경동맥을 노출. </li></ol></li><li> 풍선 카테터의 소개 <ol><li> 일반적인 경동맥 A의 근위 봉합을 후퇴rtery와 일시적으로 혈액의 흐름을 중지 선박에 동맥 클램프를 놓습니다. 가능한 봉합 원위부 같은 위치에서 외부 경동맥에 절개 작은 (동맥의 원주의​​ 1/4 1/3)을 만든다. </li><li> 조심스럽게 절개로 미 - 팽창 풍선 카테터를 삽입 한 후 경동맥에 동맥 클램프에 가까운 루멘에 카테터를 진행합니다. 클램프를 제거하고 추가 절개에서 약 35~40mm, 대동맥 궁에 풍선 카테터를 진행합니다. </li></ol></li><li> 풍선 부상 <ol><li> 수동 연결된 주사기를 통해 0.02 ㎖의 부피로 팽창 카테터 후 주사기 카테터의 콕을 잠글. 천천히 회전에 카테터를 철회. 카테터가 arteriotomic 절개에 가까운 경우, 풍선을 수축. 다시 원래 위치로 카테터를 진행합니다. </li><li> 총 3 회 2.4.1를 반복합니다. 조심스럽게 동맥 내강에서 카테터를 제거합니다. </li></ol></li><li> 외과 상처를 닫습니다 <ol><li> 봉합으로 arteriotomy를 닫습니다. 혈액의 흐름을 복원하기 위해 내부 경동맥을 놓습니다. 동맥 출혈이나 누출이 있는지 확인합니다. 출혈이 발생하는 경우, 지혈을 위해 약간 압력 거즈를 적용한다. </li><li> 절차에 사용되는 봉합 및 클램프의 나머지 부분을 제거합니다. 6.0 봉합과 선의 조직을 닫습니다. 피부 봉합이나 상처 클립으로 피부를 닫습니다. 이소 플루 란을 끄고 몇 분 동안 순수 산소와 동물을 둡니다. </li></ol></li></ol> 치료 3. 관리, 진통제, 수술 후 관리 및 안락사 <ol><li> 치료 및 진통제의 투여. <ol><li> 수술 후, (0.03 ㎎ / ㎏) 근육 부 프레 노르 핀을 주입. 수술 중 혈액 손실을 보상하기 위해 5 ml의 사전 예열 멸균 식염수 피하 주사. 복막에 sRAGE (0.5 NG의 /의 g) (치료제)를 주입한다. </li><li> OPH 다시 눈을 적셔thalmic 연고. 열 패드에 쥐를 배치하고 흉골 드러 누움을 유지하기 위해 완전한 의식을 회복 할 때까지 동물을 모니터링 할 수 있습니다. </li><li> 깨끗한 침구와 케이지에 쥐를 돌려 다시 동식물 사육장에 케이지를 가져온다. 담당 수의사와 관리인을 경고하기 위해 새장에 특별한 관찰 카드를 놓습니다. </li></ol></li><li> 수술 후 정리 <ol><li> 휴지통 또는 특별 처분 용기에 두 바늘 등 패드, 면봉을 포함하여 사용되는 수술 재료를 넣습니다. 수술 플랫폼을 소독하고 수술 도구를 청소하십시오. </li></ol></li><li> 수술 후 케어 <ol><li> 48 시간 수술 후 기간 동안 프레 노르 핀 (0.03 ㎎ / ㎏) 하루에 두 번 (입찰)을 관리 할 수​​ 있습니다. 이러한 부동, 공급 불능, hutched 자세, 주름 장식 모피와 얼굴을 찡 그리기와 같은 고통의 일반적인 징후에 대한 48 시간 수술 후 기간 동안 밀접하게 동물을 모니터링합니다. 상처 빨갛게 조건, 부종, 열개, 감염을 모니터링합니다. 노트:추가 치료는 의사의 권고에 참석에 따라 규정 될 수있다. </li><li> 수의사의 권고에 참석에 따른 봉합이나 상처 클립을 제거합니다. </li></ol></li><li> 안락사 <ol><li> 2 주 수술 후, (22)를 분석하여 사후 히스-형태에 대한 경동맥 동맥을 분리하기 위해 쥐를 안락사. 5-20%의 이소 플루 란은 호흡의 완전한 중단까지 최소 2 분 동안 공기를 포화 포함하는 챔버에서 쥐를 놓습니다. 이전 기관 및 조직의 해부에 죽음을 확인합니다. </li></ol></li></ol>

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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 Mol Med. 139, 1-30 (2007).</li><li>Zhang, W., Trebak, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Vascular+balloon+injury+and+intraluminal+administration+in+rat+carotid+artery.">Vascular balloon injury and intraluminal administration in rat carotid artery.</a> J Vis Exp. (94), (2014).</li><li>Tae, H. 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=Vessel+ultrasound+sonographic+assessment+of+soluble+receptor+for+advanced+glycation+end+products+efficacy+in+a+rat+balloon+injury+model.">Vessel ultrasound sonographic assessment of soluble receptor for advanced glycation end products efficacy in a rat balloon injury model.</a> Curr Ther Res Clin Exp. 76, 110-115 (2014).</li><li>Tae, H. 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=Chronic+treatment+with+a+broad-spectrum+metalloproteinase+inhibitor,+doxycycline,+prevents+the+development+of+spontaneous+aortic+lesions+in+a+mouse+model+of+vascular+Ehlers-Danlos+syndrome.">Chronic treatment with a broad-spectrum metalloproteinase inhibitor, doxycycline, prevents the development of spontaneous aortic lesions in a mouse model of vascular Ehlers-Danlos syndrome.</a> J Pharmacol Exp Ther. 343 (1), 246-251 (2012).</li><li>Sakaguchi, 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=Central+role+of+RAGE-dependent+neointimal+expansion+in+arterial+restenosis.">Central role of RAGE-dependent neointimal expansion in arterial restenosis.</a> J Clin Invest. 111 (7), 959-972 (2003).</li></ol>

저자는 더 경쟁 재정적 이해 관계가 없음을 선언합니다.

경동맥 동맥 내강의 벽화 내피 세포를 제거하는 부상을 생성하기 위해 풍선을 팽창하는 데 사용되는 두 가지 방법이 있었다. 하나는 액체 (20)에 부착 된 주사기를 채우기 위하여, 그리고 다른 하나는 공기 압력 (21)을 사용하는 것이다. 우리는 정확한 액량 (0.02 mL)을 각각의 방법에 사용되기 때문에, 액체로 채워진 주사기를 사용하는 것을 선호한다. 이 절차를 진행 각 동물의 부상 ?...

혈관 성형술은 동맥 경화증과 같은 병리학 적 조건에서 결과 좁아진 또는 방해 동맥을 확대하는 데 사용되는 혈관 절차입니다. 혈관 성형술 중 하나 흔한 합병증은 수술 부상과 이후의 염증에 의한 혈관 리모델링으로 인해 발생 후 운영 신생 내막의 증식, 또는 재 협착이다. 이러한 조건은 혈관 부드러운 세포 및 여러 병태 생리 학적 결과 1-3의 확산으로 이어질. 신생 내막의 증식 용기를 재 - 두껍게하고, 제 1 년 이내에 60 % 후 혈관 성형술 환자까지에서 발생합니다. 따라서, 재 협착은 널리 사용되는 혈관 성형 절차 (4)의 큰 방해가된다. 약물 용출 스텐트의 주입이 재 협착을 방지하는 데 도움이 될 수 있지만, 선택된 후보는이 비용이 많이 드는 절차 (5)를받을 수 있습니다. 동물과 임상 연구 모두 만성 염증이 vascu에 의해 생성 된 것을 설립LAR 부상 및 / 또는 수술 상처 후 혈관 신생 내막의 성장 2,4-의 주요 자극 역할을합니다. 따라서, 쥐 풍선 경동맥 손상 모델을 모방 임상 적 상황과 혈관 재 형성 및 혈관 증식 6-9에 관련된 세포 계수를 식별하기위한 유용한 모델 시스템으로서 기능한다. 이 모델 시스템은 전임상 연구 병진 10-14에서 신생 내막 성장을 억제 약물 및 치료 시약 매우 유용한 평가 도구 및 / 또는 스크린이다. 뮤린 경동맥 와이어 손상 모델 (15) 및 쥐의 대퇴 동맥 와이어 손상 모델 (16), 쥐 경동맥 풍선 손상 모델이 입은 부상의 재현을 용이하게 시술의 용이성을 위해 크기가 충분히 큰 있다는 장점을 가진다 비교. 그것은 되어온 대 일차 전지의 더 큰 개수 (예, 혈관 평활근 세포, 내피 세포)를 제공 할 수있다하는 ional는 시험 관내 연구 혈관 재 형성을 지배하는 분자 메커니즘을 묘사하기. 중요한 것은, 마우스에 비해 래트는 생리 학적 연구 (17)을위한 더 나은 모델이 알려져있다. 래트 모델의 단점 또는 제한 유전자 변형 유전자 녹아웃 모델의 부족이지만, 이러한 단점은 래트 게놈 시퀀스의 가용성 및 렌더링 CRISPR-CAS 기술 강력한 게놈 편집 도구의 최근 발전에 의해 극복 될 수있다 다른 모델 시스템 (18, 19)의 게놈 서열의 광대 한 범위의 수 조작. 쥐 풍선 손상 모델이 여러 연구소 및 다양한 포괄적 인 프로토콜에 의해 사용되었지만 (20, 21)을 발표 한,이 프로토콜은 사전 수술 준비에 대한 자세한 내용을 제공하는 것을 목적으로이 수술 연습을 설정하려면이 절차에 새로운 연구를 안내 할 수 있습니다. 우리는 또한 t의 수술 후 관리를 강조살아있는 동물 13,22에서뿐만 아니라 동맥 리모델링에 대한 치료 효과의 사후 병리 및 histomorphological 분석뿐만 아니라, 초음파 초음파 연구 허용 그는 동물.

<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.

2 주 풍선 손상 후, 래트를 안락사되고 경동맥은 히스 - 형태 학적 분석을 위해 분리된다. 모두 왼쪽 경동맥 및 취소 운영 오른쪽 동맥 처리, 단면 크로스, 파라핀 내장되어 운영했다. 파라핀 샘플은 더 얇은 단면 및 헤 마톡 실린 - 에오신 (H &amp; E) 염색을합니다. 히스 - 형태소 분석은 디지털 이미지 분석 시스템을 이용하여 수행된다. 동맥 수확 히스 - 형태소 분석의 상세 <s...

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.

생쥐 경동맥 풍선 손상 모델은 반대로 혈관 리모델링의 치료를 테스트하는

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

Research

JoVE Journal

Medicine

8.7K 조회수.  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. 

비디오: 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.

부분 결합하여 마우스 경동맥 동맥에있는 방해 흐름 유발 죽상 경화증과 경동맥 내피로부터 RNA 분리의 간단한 방법의 모델

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

연구

의학

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.

Microvascular 기능 및 리모델링에 Arteriolar 결합의 영향을 평가하기 위해 손쥐 Spinotrapezius 모델

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.

재 협착의 연구에 대한 경동맥 스텐트 시술의 쥐과 모형

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.

쥐 경동맥의 혈관 풍선 부상과 관내 관리

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.

혈관 주위 약물 전달 패치의 주입과 대퇴 동맥 와이어 부상의 쥐 모델

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.

마우스에서 가속 죽상 경화증의 유도: "와이어 부상" 모델

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.

쥐 모델에서 Infrarenal 복부 대동맥 클램핑에 의해 재현 동맥 발가 벗김 부상

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.

가속된 동맥 경화의 토끼 모델: 장 골 동맥 풍선 상해의 방법 론 적 관점

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.

쥐 경동맥 압력 제어 세그먼트 풍선 부상 과식 치료 응용 프로그램

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.

소뇌 대동맥 파열 상해 : 효율적<em&gt; In Vivo</em&gt; 평활근 세포 증식과 내피 기능 모델

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