Stenosis progression after surgical injury in Milan hypertensive rat carotid arteries

Forte, Amalia; Esposito, Salvatore; Feo, Marisa De; Galderisi, Umberto; Quarto, Cesare; Esposito, Ferdinando; Renzulli, Attilio; Berrino, Liberato; Cipollaro, Marilena; Agozzino, L; Cotrufo, Maurizio; Rossi, Francesco; Cascino, A.

doi:10.1016/j.cardiores.2003.08.015

Cited by 8 publications

(9 citation statements)

References 37 publications

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“…In this study we complement and extend previous analyses by evaluating the efficacy of c-Myc phosphorothioate (PS) AS ODNs in limiting the stenosis induced in the rat carotid by an arteriotomy model we previously characterized in different rat strains [17,18,19]. In this model, injury is induced by an asymmetric cut followed by a fine suture, thus involving the whole thickness of the vascular wall.…”

Section: Introductionmentioning

confidence: 71%

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c-Myc Antisense Oligonucleotides Preserve Smooth Muscle Differentiation and Reduce Negative Remodelling following Rat Carotid Arteriotomy

Forte¹,

Galderisi²,

Feo³

et al. 2005

J Vasc Res

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Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense (AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis (deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry (image analysis) were determined 2, 5 and 30 days after injury, respectively. Results: AS ODNs induced a 60% decrease of target c-Myc mRNA 4 h after surgery in comparison to control sense (S) and scrambled ODN-treated carotids (p < 0.05). A significant 37 and 50% decrease in SM22 protein in the media of S ODN-treated and untreated carotids was detected when compared to uninjured contralateral arteries (p < 0.05). This reduction in SM22 expression was prevented in AS ODN-treated carotids. Stenosis was mainly due to adventitial constrictive remodelling. Lumen area in AS ODN-treated carotids was 35% greater than in control arteries 30 days after surgery (p < 0.05). TUNEL assay revealed increased apoptosis in AS ODN-treated carotids (p < 0.05). Conclusions: c-Myc AS ODNs reduce arteriotomy-induced negative remodelling. This is accompanied by maintained SMC differentiation and greater apoptosis. The combination of reduced c-Myc-induced proliferation and increased apoptosis may thus underlie the less severe remodelling upon treatment with c-Myc mRNA AS ODN.

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Section: Introductionmentioning

confidence: 71%

“…The surgical injury model we applied to rat common carotid artery was performed as already published [17,18,19]. Briefly, a plastic Scanlom clamp for coronary artery bypass grafting was placed for 10 s on the carotid artery in order to cause a crushing lesion to the vessel.…”

Section: Methodsmentioning

confidence: 99%

c-Myc Antisense Oligonucleotides Preserve Smooth Muscle Differentiation and Reduce Negative Remodelling following Rat Carotid Arteriotomy

Forte¹,

Galderisi²,

Feo³

et al. 2005

J Vasc Res

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“…19,20 Figure 3 Concentration-response curve to norepinephrine in the different groups of rats. ANOVA Po0.001 between MHS and all the remaining groups.…”

Section: Discussionmentioning

confidence: 99%

“…19 Established hypertension is usually associated with the presence of structural alterations in small resistance arteries. 21 These alterations are characterized by an increase in the thickness of the tunica media layers and by a reduction in the internal diameter.…”

Section: Adducin and Small Artery Remodeling D Rizzoni Et Almentioning

confidence: 99%

Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats

et al. 2009

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The Milan hypertensive rat strain (MHS) is a genetic strain in which cardiovascular phenotypes seem to be dependent, at least in part, on adducin gene polymorphisms. The aim of our study was to evaluate the structure, contractile responses and endothelium-dependent vasodilation in mesenteric small resistance arteries in 12-week-old MHS, (n¼7), age-matched Milan normotensive rats (MNS, n¼7) and congenic strains in which the DNA segments carrying the a-adducin locus from the MHS have been introgressed into the MNS (MNA, n¼7). Systolic blood pressure (tail cuff) and left ventricular weight to body weight were measured. Mesenteric small arteries were dissected and mounted on a micromyograph; the media:lumen ratio was then calculated. Concentration-response curves to acetylcholine and to norepinephrine (NE) were created. Systolic blood pressure was significantly increased in the MHS and MNA strains compared with the MNS. No significant difference in mesenteric small resistance artery structure was observed among the groups; however, a slightly more elevated media:lumen ratio was observed in MNA compared with the MNS. In contrast, left ventricular weight to body weight was significantly increased and ACH-induced dilatation was significantly impaired in the MHS and in MNA compared with MNS. The concentration-response curve to NE in the MHS showed significantly reduced sensitivity to NE; however, maximum contraction was increased in the MHS vs. the other groups. The MHS presents cardiac (but not vascular) remodeling, endothelial dysfunction and a peculiar contractile response to NE, compared with the other groups. The systolic blood pressure increase and trend to vascular remodeling in MNA support the pathogenic role of a-adducin.

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“…Observations in contralateral uninjured arteries following unilateral carotid surgery would be expected to elucidate such systemic effects. In a previous study [3], we set up a model of rat carotid arteriotomy that mimics the injury affecting the arteries of patients subjected to endarterectomy rather than the trauma induced by standard balloon angioplasty. Our investigations, together with other studies based on a deep vascular injury [4,5], support the key role of the adventitia and perivascular tissues in arterial stenosis.…”

Section: Introductionmentioning

confidence: 99%

Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries

et al. 2008

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Vascular surgery aimed at stenosis removal induces local reactions often leading to restenosis. Although extensive analysis has been focused on pathways activated in injured arteries, little attention has been devoted to associated systemic vascular reactions. The aim of the present study was to analyse changes occurring in contralateral uninjured rat carotid arteries in the acute phase following unilateral injury. WKY (Wistar-Kyoto) rats were subjected to unilateral carotid arteriotomy. Contralateral uninjured carotid arteries were harvested from 4 h to 7 days after injury. Carotid arteries were also harvested from sham-operated rats and uninjured rats. Carotid morphology and morphometry were examined. Affymetrix microarrays were used for differential analysis of gene expression. A subset of data was validated by real-time RT-PCR (reverse transcription-PCR) and verified at the protein level by Western blotting. A total of 1011 genes were differentially regulated in contralateral uninjured carotid arteries from 4 h to 7 days after arteriotomy (P<0.0001; fold change, >or=2) and were classified into 19 gene ontology functional categories. To a lesser extent, mRNA variations also occurred in carotid arteries of sham-operated rats. Among the changes, up-regulation of members of the RAS (renin-angiotensin system) was detected, with possible implications for vasocompensative mechanisms induced by arteriotomy. In particular, a selective increase in the 69 kDa isoform of the N-domain of ACE (angiotensin-converting enzyme), and not the classical somatic 195 kDa isoform, was observed in contralateral uninjured carotid arteries, suggesting that this 69 kDa isoenzyme could influence local AngII (angiotensin II) production. In conclusion, systemic reactions to injury occur in the vasculature, with potential clinical relevance, and suggest that caution is needed in the choice of controls during experimental design in vivo.

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Stenosis progression after surgical injury in Milan hypertensive rat carotid arteries

Abstract: The injury applied to MHS carotids induces negative remodelling and a limited apoptotic reaction. These findings could arise from the balancing among proliferative factors, apoptosis-related molecules and relaxant anti-proliferative receptors, all stimulated by the injury.

Cited by 8 publications

References 37 publications

c-Myc Antisense Oligonucleotides Preserve Smooth Muscle Differentiation and Reduce Negative Remodelling following Rat Carotid Arteriotomy

c-Myc Antisense Oligonucleotides Preserve Smooth Muscle Differentiation and Reduce Negative Remodelling following Rat Carotid Arteriotomy

Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats

Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries

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