Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice

Thüsen, Jan H. von der; Berkel, Theo J.C. Van; Biessen, Erik A.L.

doi:10.1161/01.cir.103.8.1164

Cited by 206 publications

(221 citation statements)

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“…Low‐density lipoprotein receptor–deficient mice develop atherosclerosis, especially when fed a lipid‐rich diet. However, they do not spontaneously develop apparent structural changes in the arteries and require placement of perivascular carotid collar for the development of carotid stenosis 20. Other surgically induced models include mice subjected to a perivascular carotid collar placed around artery and an inflatable balloon‐induced inner lumen injury.…”

Section: Discussionmentioning

confidence: 99%

Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Hattori

Enmi

Iguchi

et al. 2016

JAHA

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BackgroundExisting rodent models of vascular cognitive impairment (VCI) show abrupt changes in cerebral blood flow (CBF) and do not reliably replicate the clinical pathogenesis of VCI. We therefore aimed to develop a mouse model of VCI where CBF is gradually reduced, followed by subsequent progressive motor and cognitive impairment, after surgical intervention.Methods and ResultsAdult C57BL/6J male mice were subjected to gradual common carotid artery stenosis (GCAS) surgery by using an ameroid constrictor vessel‐constricting device with an inner diameter of 0.75 mm. The common carotid arteries narrowed gradually after gradual constriction of ameroid constrictors over 28 days after GCAS, with subsequent 79.3% area stenosis as a result of smooth muscle cell proliferation and macrophage infiltration in the tunica intima. The 28‐day survival rate was 91%. Arterial spin labeling demonstrated gradual and continuous reduction of cortical and subcortical CBF (ratio to the preoperative value) to 54.6% and 51.5%, respectively, over 28 days. However, magnetic resonance angiography showed increment of collateral flow signals in the leptomeningeal artery. Rarefaction and proliferation of astrocytes and microglia, with loss of oligodendrocytes, were found in the white matter at 32 days. Hippocampal neuronal loss was observed in only 25% of GCAS mice, consistent with lack of abnormalities in the Morris water maze test. The rotarod test showed motor impairment, and the Y‐maze test showed working memory deficits.ConclusionsThe GCAS model successfully generated gradual and continuous CBF reduction over 28 days, with replication of key histological, radiological, and behavioral features associated with cerebral hypoperfusion leading to VCI.

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Section: Discussionmentioning

confidence: 99%

Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Hattori

Enmi

Iguchi

et al. 2016

JAHA

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“…11,36 In agreement with our findings, increased eNOS protein has previously been reported in the endothelium of the collared high-shear segments of the murine carotid artery collar model that was used in this study, thus correlating increased eNOS with increased LKLF expression in vivo. 19 In addition, LKLF and eNOS expression are positively correlated with calculated high-shear levels in the developing embryonic chicken heart and negatively correlated with endothelin-1 expression, 37 which we show here to be transcriptionally repressed by LKLF. Finally, direct proof for transcriptional induction of functional eNOS by LKLF at the promoter level was recently demonstrated in vitro.…”

Section: Discussionmentioning

confidence: 51%

“…19 For in situ hybridization, male Apo E Ϫ/Ϫ mice of 20 weeks of age were fed a semisynthetic Western-type diet. After 2 weeks, constrictive collars (diameter, 0.3 mm; length, 2 mm) were placed around both carotid arteries.…”

Section: Murine Carotid Artery Collar Modelmentioning

confidence: 99%

“…Therefore, we have used a well-defined mouse model, in which partly constrictive collars are placed around both carotid arteries, to locally increase endothelial shear stress in vivo (see Figure 5A). 19 The fold increase in endothelial shear stress is proportional to the fold decrease in lumen diameter, which is caused by placement of the collar, raised to the third power assuming constant flow, ie, an ϳ50% decreased lumen diameter will lead to an approximately eightfold increase in shear stress. We performed LMM and real-time RT-PCR to accurately assess the effect of flow on the expression of LKLF in the endothelium of the murine carotid arteries.…”

Section: Lklf Is Induced By Flow In a Murine Carotid Artery Collar Modelmentioning

confidence: 99%

“…15,18 To gain more insight into the potential flow-mediated spatial expression of LKLF in endothelial cells, we have studied its detailed in vitro biomechanical regulation and in vivo expression in various human vascular tissues. Using a mouse model in which endothelial shear stress can be locally increased, 19 the moderate basal expression of endothelial LKLF was shown to be elevated by shear stress in vivo. Overexpression and knockdown of LKLF in HUVECs revealed that the flow-responsive genes that are involved in the regulation of vascular tone are under transcriptional control of LKLF.…”

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Endothelial KLF2 Links Local Arterial Shear Stress Levels to the Expression of Vascular Tone-Regulating Genes

Dekker

Thienen

Rohlena

et al. 2005

The American Journal of Pathology

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316

289

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Lung Krüppel-like factor (LKLF/KLF2) is an endothelial transcription factor that is crucially involved in murine vasculogenesis and is specifically regulated by flow in vitro. We now show a relation to local flow variations in the adult human vasculature: decreased LKLF expression was noted at the aorta bifurcations to the iliac and carotid arteries, coinciding with neointima formation. The direct involvement of shear stress in the in vivo expression of LKLF was determined independently by in situ hybridization and laser microbeam microdissection/reverse transcriptase-polymerase chain reaction in a murine carotid artery collar model, in which a 4-to 30-fold induction of LKLF occurred at the high-shear sites. Dissection of the biomechanics of LKLF regulation in vitro demonstrated that steady flow and pulsatile flow induced basal LKLF expression 15-and 36-fold at shear stresses greater than ϳ5 dyne/cm 2 , whereas cyclic stretch had no effect. The focal development of atherosclerosis has been linked to the local variations in blood flow that are observed near the irregular blood vessel geometries of bifurcations and bends. 1,2 Continuous exposure of endothelial cells to flow in vivo generates a tangential force, shear stress, across their apical surfaces. A large number of studies support the hypothesized antiatherosclerotic effect of shear stress on the endothelium, and are mainly based on the ability of shear stress to modulate endothelial gene expression. 3 Throughout the recent years, a collection of shear stress-responsive endothelial genes has been established. 4 -8 Usually no clear distinction is made between genes induced by prolonged shear and those induced by short-term shear (Ͻ24 hours), although the latter class typically represents a general stress response also observed with turbulent flow types and seems more related to endothelial dysfunction. Based on the rationale that only genes induced by prolonged shear would represent the healthy transcriptome, we previously identified a limited number of genes that are still highly induced after exposing human umbilical vein endothelial cells (HUVECs) to flow for 7 days, but which are not induced by various other (inflammatory) stimuli. 6 The expression of one of those genes, the transcription factor lung Krü ppel-like factor (LKLF/

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Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque

Bochove¹,

Paulis²,

Segers³

et al. 2010

Contrast Media & Molecular

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Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE(-/-) mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T(1) -weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T(1) -weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6 min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets.

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Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice

Cited by 206 publications

References 22 publications

Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Endothelial KLF2 Links Local Arterial Shear Stress Levels to the Expression of Vascular Tone-Regulating Genes

Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque

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