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 border="0" cellpadding="0" cellspacing="0" width="450">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">2 F Fogarty balloon embolectomy catheter&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
			<td style="width:163px;">Edwards Lifesciences&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Standard scalpel</td>
			<td style="width:163px;">Fine Science Tools</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:287px;">Small&#160; curved forceps (Large radius Dumont#7shanks curved)&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
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			<td height="21" style="height:21px;width:287px;">Large, medium and small micro-scissors</td>
			<td style="width:163px;">Roboz</td>
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			<td height="21" style="height:21px;width:287px;">Needles (20 G)&#160;&#160;</td>
			<td style="width:163px;">TycoHealthcare</td>
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			<td height="41" style="height:41px;width:287px;">Micro-surgery forceps with micro-blunted atraumatic tips</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Atraumatic straight small arterial clamps&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
		</tr>
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			<td height="41" style="height:41px;width:287px;">Retractor&#160; with maximum spread 5.5 cm long blunt teeth</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
		</tr>
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			<td height="21" style="height:21px;width:287px;">Silk suture (4.0 and&#160; 6.0 )</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Syringe (1.0 ml)&#160;</td>
			<td style="width:163px;">BD&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Curity gauze sponges</td>
			<td style="width:163px;">AllegroMedical</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Cotton tip applicators sterile and non-sterile</td>
			<td style="width:163px;">Puritan Medical Products</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Compact hot bead sterilizer</td>
			<td style="width:163px;">Fine Science Tools</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Self-regulating heating pad</td>
			<td style="width:163px;">Fine Science Tools&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">ADS200 anesthesia system/ventilator</td>
			<td style="width:163px;">Paragon Medical</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Isoflurane (forane), liquid form</td>
			<td style="width:163px;">Baxter</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">Sodium chloride 0.9% (Saline)&#160;</td>
			<td style="width:163px;">Hospira</td>
		</tr>
		<tr height="41">
			<td height="41" style="height:41px;width:287px;">Buprenex (buprenorphine)&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</td>
			<td style="width:163px;">Reckitt Benckiser Healthcare (UK) Ltd.&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">70% alcohol</td>
			<td style="width:163px;">Fisher</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:287px;">1: 10 Betadine</td>
			<td style="width:163px;">Fisher</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

8.6K 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

Intranasal Administration of CNS Therapeutics to Awake Mice

Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects1. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport2. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials3.
Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models 4-6 and deferoxamine in Alzheimer's mouse models. 7,8
The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible.

A method to intranasally administer drugs to awake mice for the purpose of targeting the brain is described. This method allows for repeat dosing over long periods using intranasal administration of drug without anesthesia, and nose-to-brain delivery with minimal systemic exposure.

깨어 마우스로 CNS의 치료학의 비강 관리

Intranasal administration is a method of delivering  therapeutic agents to the central nervous system (CNS). It is  non-invasive and allows large ...

연구

의학

Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier1. The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells2. Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest.
The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption3. Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug4. Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory system into the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine5 and bradykinin6. This method, however, is selective primarily for the brain-tumor barrier7. Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol8. Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier9. In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients that makes it a proven tool for translational research10-12.
In order to accomplish BBBD, mannitol must be delivered at a high rate directly into the brain's arterial circulation. In humans, an endovascular catheter is guided to the brain where rapid, direct flow can be accomplished. This protocol models human BBBD as closely as possible. Following a cut-down to the bifurcation of the common carotid artery, a catheter is inserted retrograde into the ECA and used to deliver mannitol directly into the internal carotid artery (ICA) circulation. Propofol and N2O anesthesia are used for their ability to maximize the effectiveness of barrier disruption13. If executed properly, this procedure has the ability to safely, effectively, and reversibly open the blood-brain barrier and improve the delivery of drugs that do not ordinarily reach the brain 8,13,14.

Blood-brain barrier disruption aids the delivery of certain drugs to the brain. Mannitol delivered intra-arterially shrinks cells surrounding blood vessels in order to physically disrupt the barrier.

혈액 - 뇌 장벽 장애의 쥐 모델 Neurovascular 치료학 타겟이 분명한 허용하려면

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain ...

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.

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 ...

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 ...

Retroductal Submandibular Gland Instillation and Localized Fractionated Irradiation in a Rat Model of Salivary Hypofunction

Normal tissues that lie within the portals of radiation are inadvertently damaged. Salivary glands are often injured during head and neck radiotherapy. Irreparable cell damage results in a chronic loss of salivary function that impairs basic oral activities, and increases the risk of oral infections and dental caries. Salivary hypofunction and its complications gravely impact a patient's comfort. Current symptomatic management of the condition is ineffective, and newer therapies to assuage the condition are needed. 
Salivary glands are exocrine glands, which expel their secretions into the mouth via excretory ducts. Cannulation of these ducts provides direct access to the glands. Retroductal delivery of a contrast agent to major salivary glands is a routine out-patient procedure for diagnostic imaging. Using a similar procedure, localized treatment of the glands is feasible. However, performing this technique in preclinical studies with small animals poses unique challenges. In this study we describe the technique of retroductal administration in rat submandibular glands, a procedure that was refined in Dr. Bruce Baum's laboratory (NIH)1, and lay out a procedure for local gland irradiation.

Salivary gland hypofunction, a major adverse effect of head and neck radiotherapy diminishes a patient's quality of life. The demonstration of efficacy of new therapies in animal models is a prerequisite before clinical transition. This protocol describes retroductal administration and local irradiation of rat submandibular glands.

타액 기능 저하의 쥐 모델에서 Retroductal 턱밑 글 랜드 점적 및 현지화 된 분획 조사

Normal tissues that lie within the portals of radiation are inadvertently damaged. Salivary glands are often injured during head and neck radiotherapy. ...

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 ...

Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine balloon denudation model, which is comparable with established vessel injury models in large animals. The aorta denudation model with balloon catheters mimics the clinical setting and leads to comparable pathobiological and physiological changes. Briefly, after performing a horizontal incision in the aorta abdominalis, a balloon catheter will be inserted into the vessel, inflated, and introduced retrogradely. Inflation of the balloon will lead to intima injury and overdistension of the vessel. After removing the catheter, the aortic incision will be closed with single stiches. The model shown in this article is reproducible, easy to perform, and can be established quickly and reliably. It is especially suitable for evaluating expensive experimental therapeutic agents, which can be applied in an economical fashion. By using different knockout-mouse strains, the impact of different genes on MH development can be assessed.

This article demonstrates a murine model to study the development of myointimal hyperplasia (MH) after aortic balloon injury.

풍선-기반 부상 마우스 복 부 대동맥에서 Myointimal 증식을 유도 하

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine ...

A Drosophila In Vivo Injury Model for Studying Neuroregeneration in the Peripheral and Central Nervous System

The regrowth capacity of damaged neurons governs neuroregeneration and functional recovery after nervous system trauma. Over the past few decades, various intrinsic and extrinsic inhibitory factors involved in the restriction of axon regeneration have been identified. However, simply removing these inhibitory cues is insufficient for successful regeneration, indicating the existence of additional regulatory machinery. Drosophila melanogaster, the fruit fly, shares evolutionarily conserved genes and signaling pathways with vertebrates, including humans. Combining the powerful genetic toolbox of flies with two-photon laser axotomy/dendriotomy, we describe here the Drosophila sensory neuron &#8211; dendritic arborization (da) neuron injury model as a platform for systematically screening for novel regeneration regulators. Briefly, this paradigm includes a) the preparation of larvae, b) lesion induction to dendrite(s) or axon(s) using a two-photon laser, c) live confocal imaging post-injury and d) data analysis. Our model enables highly reproducible injury of single labeled neurons, axons, and dendrites of well-defined neuronal subtypes, in both the peripheral and central nervous system.

A Drosophila In Vivo Injury Model for Studying Neuroregeneration in the Peripheral and Central Nervous System

Here, we present a protocol using the Drosophila sensory neuron - dendritic arborization (da) neuron injury model, which combines in vivo live imaging, two-photon laser axotomy/dendriotomy, and the powerful fly genetic toolbox, as a platform for screening potential promoters and inhibitors of neuroregeneration.

주변에 Neuroregeneration 중앙 신 경계를 연구 하 고 대 한 Vivo에서 초파리 부상 모델

The regrowth capacity of damaged neurons governs neuroregeneration and functional recovery after nervous system trauma. Over the past few decades, various ...

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.

제 2 철 염화 유도 개 경 동맥 혈전 증: 혈관 손상의 큰 동물 모델

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

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 ...