Name: a rat model of mild intrauterine hypoperfusion with microcoil stenosis
Uploaded: 2018-01-07T14:00:00
Description: Watch this Scientific Journal Video about A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis at JoVE.com

这项工作得到了2013财政年度在 jsp 和 CNRS, jsp KAKENHI 授予数字 26860858, 和 Narishige 神经科学研究基金会的研究交流计划的支持。我们感谢 Drs 子和京子盐谷进行了有益的讨论。我们感谢玛丽 Furuta, 睦坂, 律希, 和 Dr. Emi 田中的优秀技术援助。

所有的实验都是按照日本吹国家脑和心血管中心实验动物保育和使用委员会批准的协议进行的。
1. 为 MIUH 手术准备下列动物和材料
<ol><li>在妊娠日 17, 即胚胎日 17 (E17), 准备定时妊娠大鼠。水坝的平均身体重量是307.0 ± 40.7 g (平均± SD, n = 9)。</li>
	<li>准备金属弹簧;内径0.24 毫米, 由金涂层钢制成。</li>
	<li>根据材料表准备所有材料。</li>
</ol>2. 准备 MIUH ?...

<ol>
	<li>Ohshima, 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=Mild+intrauterine+hypoperfusion+reproduces+neurodevelopmental+disorders+observed+in+prematurity.">Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity.</a> Sci Rep. 6, 39377 (2016).</li><li>Anderson, P., Doyle, L. W., Victorian Infant Collaborative Study, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neurobehavioral+outcomes+of+school-age+children+born+extremely+low+birth+weight+or+very+preterm+in+the+1990s.">Neurobehavioral outcomes of school-age children born extremely low birth weight or very preterm in the 1990s.</a> JAMA. 289 (24), 3264-3272 (2003).</li><li>Levine, T. A., 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=Early+childhood+neurodevelopment+after+intrauterine+growth+restriction:+a+systematic+review.">Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.</a> Pediatrics. 135 (1), 126-141 (2015).</li><li>Sucksdorff, 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=Preterm+Birth+and+Poor+Fetal+Growth+as+Risk+Factors+of+Attention-Deficit/+Hyperactivity+Disorder.">Preterm Birth and Poor Fetal Growth as Risk Factors of Attention-Deficit/ Hyperactivity Disorder.</a> Pediatrics. 136 (3), e599-e608 (2015).</li><li>Volpe, J. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brain+injury+in+premature+infants:+a+complex+amalgam+of+destructive+and+developmental+disturbances.">Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances.</a> Lancet Neurol. 8 (1), 110-124 (2009).</li><li>Nardozza, L. 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=Fetal+growth+restriction:+current+knowledge.">Fetal growth restriction: current knowledge.</a> Arch Gynecol Obstet. 295 (5), 1061-1077 (2017).</li><li>Chang, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preterm+birth+and+the+role+of+neuroprotection.">Preterm birth and the role of neuroprotection.</a> Bmj. 350, g6661 (2015).</li><li>Coq, J. O., Delcour, M., Massicotte, V. S., Baud, O., Barbe, M. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prenatal+ischemia+deteriorates+white+matter,+brain+organization,+and+function:+implications+for+prematurity+and+cerebral+palsy.">Prenatal ischemia deteriorates white matter, brain organization, and function: implications for prematurity and cerebral palsy.</a> Dev Med Child Neurol. 58, 7-11 (2016).</li><li>Jantzie, L. L., Corbett, C. J., Firl, D. J., Robinson, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Postnatal+Erythropoietin+Mitigates+Impaired+Cerebral+Cortical+Development+Following+Subplate+Loss+from+Prenatal+Hypoxia-Ischemia.">Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia-Ischemia.</a> Cereb Cortex. 25 (9), 2683-2695 (2015).</li><li>Kubo, K. I., 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=Association+of+impaired+neuronal+migration+with+cognitive+deficits+in+extremely+preterm+infants.">Association of impaired neuronal migration with cognitive deficits in extremely preterm infants.</a> JCI Insight. 2 (10), (2017).</li><li>Delcour, 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=Mild+musculoskeletal+and+locomotor+alterations+in+adult+rats+with+white+matter+injury+following+prenatal+ischemia.">Mild musculoskeletal and locomotor alterations in adult rats with white matter injury following prenatal ischemia.</a> Int J Dev Neurosci. 29 (6), 593-607 (2011).</li><li>Gilbert, J. S., Babcock, S. A., Granger, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hypertension+produced+by+reduced+uterine+perfusion+in+pregnant+rats+is+associated+with+increased+soluble+fms-like+tyrosine+kinase-1+expression.">Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression.</a> Hypertension. 50 (6), 1142-1147 (2007).</li><li>Granger, J. P., 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=Reduced+uterine+perfusion+pressure+(RUPP)+model+for+studying+cardiovascular-renal+dysfunction+in+response+to+placental+ischemia.">Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia.</a> Methods Mol Med. 122, 383-392 (2006).</li><li>Mazur, M., Miller, R. H., Robinson, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Postnatal+erythropoietin+treatment+mitigates+neural+cell+loss+after+systemic+prenatal+hypoxic-ischemic+injury.">Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury.</a> J Neurosurg Pediatr. 6 (3), 206-221 (2010).</li><li>Olivier, P., Baud, O., Evrard, P., Gressens, P., Verney, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prenatal+ischemia+and+white+matter+damage+in+rats.">Prenatal ischemia and white matter damage in rats.</a> J Neuropathol Exp Neurol. 64 (11), 998-1006 (2005).</li><li>Robinson, S., 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=Developmental+changes+induced+by+graded+prenatal+systemic+hypoxic-ischemic+insults+in+rats.">Developmental changes induced by graded prenatal systemic hypoxic-ischemic insults in rats.</a> Neurobiol Dis. 18 (3), 568-581 (2005).</li><li>Rice, D., Barone, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Critical+periods+of+vulnerability+for+the+developing+nervous+system:+evidence+from+humans+and+animal+models.">Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.</a> Environ Health Perspect. 108, 511-533 (2000).</li><li>Basilious, A., Yager, J., Fehlings, M. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neurological+outcomes+of+animal+models+of+uterine+artery+ligation+and+relevance+to+human+intrauterine+growth+restriction:+a+systematic+review.">Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterine growth restriction: a systematic review.</a> Dev Med Child Neurol. 57 (5), 420-430 (2015).</li><li>Delcour, 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=Neuroanatomical,+sensorimotor+and+cognitive+deficits+in+adult+rats+with+white+matter+injury+following+prenatal+ischemia.">Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia.</a> Brain Pathol. 22 (1), 1-16 (2012).</li></ol>

两个子宫角的卵巢和子宫动脉的圈狭窄在所有胎盘和胎儿中产生一致和可再生的宫内灌注。灌注的水平可以通过使用不同内径的弹簧进行修改。大鼠幼崽出生于一个大坝上, 其中动脉狭窄已执行与弹簧0.24 毫米内直径显示 IUGR 和早产 (详见参考 1)。幼崽表现出神经和行为改变, 类似于早产儿所观察到的体征和症状。这些神经的改变包括心室扩大, 皮质和胼胝体变薄, 脑重量减少, 但没有明显的细胞丢?...

胎儿宫内生长受限 (IUGR) (也称为胎生长限制) (出生体重 < 10th百分比为孕龄), 早产 (出生在 < 37 周妊娠), 和/或低出生体重 (< 2500 g) 的帐户新生儿的近 10% 2,3。许多这些婴儿存在神经问题, 如脑瘫和发育障碍 (如, 注意力缺陷/多动障碍 (ADHD) 和学习障碍) 3,4,5。这些条件在其病因和结局上有相同和不同之处。IUGR 的病因是多因素, 胎盘不足与宫内灌注被认为是最常见的原因, non-anomalous 胎儿7。早产的病因也多为多因素, 而炎是最常见的原因8。
轻度宫内灌注 (MIUH) 对大脑发育的影响尚不清楚。目前可用的动物模型宫内灌注/缺血主要涉及严重灌注或梯度程度的灌注有或没有再灌注9,10,11。然而, 在临床环境中, MIUH 的病例被认为比涉及这种严重疾病的情况更为频繁。目前可用的 MIUH 模型是一种啮齿类动物模型, 涉及子宫或卵巢动脉的缝合结扎, 以及一种涉及将双侧卵巢动脉和主动脉夹紧的啮齿动物模型, 其有通畅12,13, 14、15、16、17。这些模型的缺点之一是广泛的 inter-fetus 变异性, 从胎儿与深刻的灌注到胎儿与几乎完整的灌注, 取决于胎儿的位置在子宫动脉拱廊和卵巢动脉。这些模型的另一个缺点是他们无法区分出生后每个胎儿的位置;因此, 研究人员不能区分出生后个体小狗所经历的宫内灌注的严重性。
我们已经开发了一个大鼠模型的 MIUH 涉及多动脉狭窄1。环绕在卵巢和子宫动脉周围的直径0.24 毫米的金属微线圈会导致血管狭窄, 但不会阻塞 (图 1)。应用这些弹簧在所有供子宫的动脉的近端, 即双侧子宫和卵巢动脉, 在胚胎日 17 (相当于胚胎周20-25 在人类18) 引起显著但轻度的减少血液流向胎盘和胎儿线圈后血流的减少被应用到所有四个供子宫的动脉在每个胎盘和胎儿中基本上是相同的。胎儿死亡率低于20%。幼崽是通过自发分娩1-2 天前 (胚胎日 21-22) 比正常出生。几乎所有的幼崽出生都显着低出生体重1。灰色和白色物质体积减少, 没有明显的组织损伤1。幼崽出现延迟获得新生儿反应, 肌肉无力, 并改变自发活动1。该模型模仿早产或 IUGR 的儿童的临床症状和体征;儿童出生早产儿表现为灰质和白质体积减少或无白质损伤6, 目前神经发育延迟的里程碑, 并可能出现行为问题, 如 ADHD 的3,5;儿童与 IUGR 表现出最小的神经的变化, 并有增加的风险, 神经发育障碍, 如马达和认知延迟4,7。早产和 IUGR 是不同的条件, 但这两种情况具有基本的机制, 即在足月孕龄前对未成熟的大脑进行侮辱。

<table>
	<tbody>
		<tr>
			<td>Stereomicroscope</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane anesthesia machine</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Anesthesia induction box</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heating pad</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Diaper 30x40 cm</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Depilatory foam or shaver</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Iodine disinfectant solution</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Gauze 10x20 cm&#160;</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical drape 45x45 cm with a round opening 5 cm in diameter</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Spray bottle with ethanol for disinfection</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Cotton swab</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps with large blunt tips</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps with angled fine tips</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scissors</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical scalpel, blade size is 27mm long (no.10, Axel, AS ONE Corporation, Osaka, Japan)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical suture needle</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Metal microcoils; inner diameter 0.24 mm, made from gold-coated steel (SAMINI Co. Ltd., Shizuoka, Japan)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Silk suture 4-0</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sterile saline (0.9% sodium chloride)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heating water bath</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Plastic syringes (50ml) and needles (18G)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

a rat model of mild intrauterine hypoperfusion with microcoil stenosis

宫内灌注/缺血是宫内/胎儿生长受限、早产和低出生体重的主要原因之一。这一现象的大多数研究都是在严重的宫内缺血模型中进行的, 或者是子宫灌注的梯度度模型。未对均匀轻度宫内灌注 (MIUH) 模型进行研究。两个模型已用于研究 MIUH: 一个模型的基础上, 两侧的动脉拱廊形成的子宫和卵巢动脉, 和一个瞬态模型的基础上修剪双侧卵巢动脉和主动脉有通畅。这两个啮齿动物模型的 MIUH 有一定的局限性, 例如, 不是所有的胎儿都受到 MIUH, 取决于他们在子宫角的位置。在我们的 MIUH 模型中, 所有胎儿的宫内灌注。MIUH 是通过轻度狭窄的所有四动脉喂养子宫, 即, 双侧子宫和卵巢动脉。
动脉狭窄是由金属弹簧包裹在喂养动脉周围。产生动脉狭窄与弹簧允许我们控制, 优化和繁殖减少血流量, 很少 inter-animal 变异性和低死亡率, 从而使准确的评价。当使用内径为0.24 毫米的弹簧时, 胎盘和胎儿的血流轻度减少 (约30% 来自胎盘的 pre-stenosis 水平)。我们的 MIUH 模型的后代清楚地显示了神经、神经和行为测试结果的长期变化。

在将弹簧应用于所有供子宫的动脉, 即双侧子宫和卵巢动脉后, 所有胎儿都受到了类似的灌注。内直径为0.24 毫米的弹簧的应用导致了这些动脉的轻度狭窄, 从而导致胎盘和胎儿的血流轻度减少 (图 3; 大约30% 从胎盘的 pre-stenosis 水平, 看见参考1的详细信息)。从大坝出生的幼崽演示 IUGR (表 1)。
?...

Watch this Scientific Journal Video about A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis at JoVE.com

A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis

轻度宫内灌注是由动脉狭窄, 金属弹簧包裹周围的子宫和卵巢动脉在大鼠胚胎日17。这一程序产生了产前灌注和宫内生长的限制。

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