This study was supported in part by the Deutsche Forschungsgemeinschaft (DFG), project GZ PI 771/1-1; SFB 656 "Cardiovascular Molecular Imaging," M&uuml;nster, Germany (projects C6, Z2, B3, and PM3); EU NoE "Diagnostic Molecular Imaging&mdash;DIMI" (WP 11.1 and 11.2). The study was also funded in part by the British Heart Foundation, UK.

1. Preparing the shear stress modifier (cuff)
<ol>
	<li>The shear stress modifier consists of two longitudinal halves of a cylinder with a cone shaped lumen. The half shells are made of thermoplastic polyetherketone produced by a plastic casting procedure. The cast elements are sent out while still connected to the runner. Hence, the half shells have to be cut off before usage. Each cast contains half shells of different sizes ranging from 150 &mu;m - 300 &mu;m (lowest inner diameter at downstream en...

<ol>
	<li>Chiu, J. J., Chien, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+disturbed+flow+on+vascular+endothelium:+pathophysiological+basis+and+clinical+perspectives.">Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives.</a> Physiol. Rev. 91, 327-387 (2011).</li><li>Cunningham, K. S., Gotlieb, A. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+role+of+shear+stress+in+the+pathogenesis+of+atherosclerosis.">The role of shear stress in the pathogenesis of atherosclerosis.</a> Lab. Invest. 85, 9-23 (2005).</li><li>Ali, F., Zakkar, M., Karu, K., Lidington, E. A., Hamdulay, S. S., Boyle, J. J., Zloh, M., Bauer, A., Haskard, D. O., Evans, P. C., Mason, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Induction+of+the+cytoprotective+enzyme+heme+oxygenase-1+by+statins+is+enhanced+in+vascular+endothelium+exposed+to+laminar+shear+stress+and+impaired+by+disturbed+flow.">Induction of the cytoprotective enzyme heme oxygenase-1 by statins is enhanced in vascular endothelium exposed to laminar shear stress and impaired by disturbed flow.</a> J. Biol. Chem. 284, 18882-18892 (2009).</li><li>Hastings, N. E., Simmers, M. B., McDonald, O. G., Wamhoff, B. R., Blackman, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atherosclerosis-prone+hemodynamics+differentially+regulates+endothelial+and+smooth+muscle+cell+phenotypes+and+promotes+pro-inflammatory+priming.">Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming.</a> Am. J. Physiol. Cell. Physiol. 293, C1824-C1833 (2007).</li><li>Zheng, J., Abendschein, D. R., Okamoto, R. J., Yang, D., McCommis, K. S., Misselwitz, B., Gropler, R. J., Tang, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MRI-based+biomechanical+imaging:+initial+study+on+early+plaque+progression+and+vessel+remodeling.">MRI-based biomechanical imaging: initial study on early plaque progression and vessel remodeling.</a> Magn. Reson. Imaging. 27, 1309-1318 (2009).</li><li>Stone, P. H., Coskun, A. U., Kinlay, S., Clark, M. E., Sonka, M., Wahle, A., Ilegbusi, O. J., Yeghiazarians, Y., Popma, J. J., Orav, J., Kuntz, R. E., Feldman, C. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+endothelial+shear+stress+on+the+progression+of+coronary+artery+disease,+vascular+remodeling,+and+in-stent+restenosis+in+humans:+in+vivo+6-month+follow-up+study.">Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study.</a> Circulation. 108, 438-444 (2003).</li><li>Pedersen, E. M., Oyre, S., Agerbaek, M., Kristensen, I. B., Ringgaard, S., Boesiger, P., Paaske, W. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Distribution+of+early+atherosclerotic+lesions+in+the+human+abdominal+aorta+correlates+with+wall+shear+stresses+measured+in+vivo.">Distribution of early atherosclerotic lesions in the human abdominal aorta correlates with wall shear stresses measured in vivo.</a> Eur. J. Vasc. Endovasc. Surg. 18, 328-333 (1999).</li><li>Buchanan, J. R., Kleinstreuer, C., Truskey, G. A., Lei, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Relation+between+non-uniform+hemodynamics+and+sites+of+altered+permeability+and+lesion+growth+at+the+rabbit+aorto-celiac+junction.">Relation between non-uniform hemodynamics and sites of altered permeability and lesion growth at the rabbit aorto-celiac junction.</a> Atherosclerosis. 143, 27-40 (1999).</li><li>Nam, D., Ni, C. W., Rezvan, A., Suo, J., Budzyn, K., Llanos, A., Harrison, D., Giddens, D., Jo, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Partial+carotid+ligation+is+a+model+of+acutely+induced+disturbed+flow,+leading+to+rapid+endothelial+dysfunction+and+atherosclerosis.">Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis.</a> Am. J. Physiol. Heart. Circ. Physiol. 297, 1535-1543 (2009).</li><li>Cheng, C., van Haperen, R., de Waard, M., van Damme, L. C., Tempel, D., Hanemaaijer, L., van Cappellen, G. W., Bos, J., Slager, C. J., Duncker, D. J., van der Steen, A. F., de Crom, R., Krams, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Shear+stress+affects+the+intracellular+distribution+of+eNOS:+direct+demonstration+by+a+novel+in+vivo+technique.">Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique.</a> Blood. 106, 3691-3698 (2005).</li><li>Cheng, C., Tempel, D., van Haperen, R., van der Baan, A., Grosveld, F., Daemen, M. J., Krams, R., de Crom, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atherosclerotic+lesion+size+and+vulnerability+are+determined+by+patterns+of+fluid+shear+stress.">Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress.</a> Circulation. 113, 2744-2753 (2006).</li><li>van Bochove, G. S., Straathof, R., Krams, R., Nicolay, K., Strijkers, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MRI-determined+carotid+artery+flow+velocities+and+wall+shear+stress+in+a+mouse+model+of+vulnerable+and+stable+atherosclerotic+plaque.">MRI-determined carotid artery flow velocities and wall shear stress in a mouse model of vulnerable and stable atherosclerotic plaque.</a> MAGMA. 23, 77-84 (2010).</li><li>Cuhlmann, S., Van der Heiden, K., Saliba, D., Tremoleda, J. L., Khalil, M., Zakkar, M., Chaudhury, H., Luong, L. A., Mason, J. C., Udalova, I., Gsell, W., Jones, H., Haskard, D. O., Krams, R., Evans, P. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Disturbed+Blood+Flow+Induces+RelA+Expression+via+c-Jun+N-Terminal+Kinase+1:+A+Novel+Mode+of+NF-{kappa}B+Regulation+That+Promotes+Arterial+Inflammation.">Disturbed Blood Flow Induces RelA Expression via c-Jun N-Terminal Kinase 1: A Novel Mode of NF-{kappa}B Regulation That Promotes Arterial Inflammation.</a> Circ. Res. 108, (2011).</li></ol>

The authors have nothing to disclose.

In order to minimize experimental variation it is recommended to work with animals of nearly the same age and with the same diet history. A recently published investigation demonstrates that the shear stress modifier applied in wildtype mice might be a good model for the investigation of endothelial dysfunction and early inflammatory responses induced by altered flow dynamics 13. However, for the enquiry of atherosclerotic plaque development transgenic hyperlipidemic mouse models (e.g. the ApoE knockout mouse)...

<table border="1">
<tbody>
 <tr>
 <td>Name</td>
 <td>Company</td>
 <td>Comments </td>
 </tr>
 <tr>
 <td>Shear stress modifier (polyetherketone)</td>
 <td>Promolding BV
 <a href="http://promolding.nl">http://promolding.nl</a></td>
 <td>The casts are sent out while still connected to the runner. Thus, the single elements have to be cut off before usage.</td>
 </tr>
</tbody>
</table>

implantation of a carotid cuff for triggering shear-stress induced atherosclerosis in mice

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce atherosclerosis (reviewed in 1 and 2). The role of shear stress has been extensively studied in vitro investigating the influence of flow dynamics on cultured endothelial cells 1,3,4 and in vivo in larger animals and humans 1,5,6,7,8. However, highly reproducible small animal models allowing systematic investigation of the influence of shear stress on plaque development are rare. Recently, Nam et al. 9 introduced a mouse model in which the ligation of branches of the carotid artery creates a region of low and oscillatory flow. Although this model causes endothelial dysfunction and rapid formation of atherosclerotic lesions in hyperlipidemic mice, it cannot be excluded that the observed inflammatory response is, at least in part, a consequence of endothelial and/or vessel damage due to ligation.
In order to avoid such limitations, a shear stress modifying cuff has been developed based upon calculated fluid dynamics, whose cone shaped inner lumen was selected to create defined regions of low, high and oscillatory shear stress within the common carotid artery 10. By applying this model in Apolipoprotein E (ApoE) knockout mice fed a high cholesterol western type diet, vascular lesions develop upstream and downstream from the cuff. Their phenotype is correlated with the regional flow dynamics 11 as confirmed by in vivo Magnetic Resonance Imaging (MRI) 12: Low and laminar shear stress upstream of the cuff causes the formation of extensive plaques of a more vulnerable phenotype, whereas oscillatory shear stress downstream of the cuff induces stable atherosclerotic lesions 11. In those regions of high shear stress and high laminar flow within the cuff, typically no atherosclerotic plaques are observed.
 
In conclusion, the shear stress-modifying cuff procedure is a reliable surgical approach to produce phenotypically different atherosclerotic lesions in ApoE-deficient mice.

Watch this Scientific Journal Video about Implantation of a Carotid Cuff for Triggering Shear-stress Induced Atherosclerosis in Mice at JoVE.com

Implantation of a Carotid Cuff for Triggering Shear-stress Induced Atherosclerosis in Mice

The constricting cuff presented in this article is designed to induce atherosclerosis in the murine common carotid artery. Due to the conical shape of its inner lumen the implanted cuff generates well-defined regions of low, high and oscillatory shear stress triggering the development of atherosclerotic lesions of different inflammatory phenotypes.

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce ...

implantation-carotid-cuff-for-triggering-shear-stress-induced

Research

JoVE Journal

Medicine

19.9K Views.  Westfälische Wilhelms-University Münster. The constricting cuff presented in this article is designed to induce atherosclerosis in the murine common carotid artery. Due to the conical shape of its inner lumen the implanted cuff generates well-defined regions of low, high and oscillatory shear stress triggering the development of atherosclerotic lesions of different inflammatory phenotypes.