Rabbit Carotid Artery Research Articles

Tissue response to poly( l-lactic acid)-based blend with phospholipid polymer for biodegradable cardiovascular stents

A temporary cardiovascular stent device by bioabsorbable materials might reduce late stent thrombosis. A water-soluble amphiphilic phospholipid polymer bearing phosphorylcholine groups (PMB30W) was blended with a high-molecular-weight poly( l-lactic acid) (PLLA) to reduce unfavorable tissue responses at the surface. The PLLA implants and the polymer blend (PLLA/PMB30W) implants were inserted into subcutaneous tissues of rats, the infrarenal aorta of rats, and the internal carotid arteries of rabbits. After 6 months subcutaneous implantation, the PLLA/PMB30W maintained high density of phosphorylcholine groups on the surface without a significant bioabsorption. After intravascular implantation, the cross-sectional areas of polymer tubing with diameters less than 1.6 mm were histomorphometrically measured. Compared to the PLLA tubing, the PLLA/PMB30W tubing significantly reduced the thrombus formation during 30 d of implantation. Human peripheral blood mononuclear cells were cultured on the PLLA and the PLLA/PMB30W to compare inflammatory reactions. Enzyme-linked immunosorbent assay quantified substantially decreased proinflammatory cytokines in the case of the PLLA/PMB30W. They were almost the same level as the negative controls. Thus, we conclude that the phosphorylcholine groups could reduce tissue responses significantly both in vivo and in vitro, and the PLLA/PMB30W is a promising material for preparing temporary cardiovascular stent devices.

Adipokine Resistin Is a Key Player to Modulate Monocytes, Endothelial Cells, and Smooth Muscle Cells, Leading to Progression of Atherosclerosis in Rabbit Carotid Artery

We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms. Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified. We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed. Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Peri-adventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 × vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo. Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis.

Experimental characterization of the distribution of collagen fiber recruitment

The passive biomechanical behavior of blood vessels is generally modeled by a parallel arrangement of elastin and collagen, with collagen recruitment depending on vessel strain. We experimentally determined the collagen recruitment distribution using confocal microscopy. Digital images from sections of rabbit carotid artery under increasing circumferential stretch ratio were acquired. The straightness of the fibers was measured to compute the fraction of recruited fibers for each stretch ratio. The experimental distribution obtained was then used in the model proposed by Zulliger et al. This model is based on a strain energy function (SEF), which provides a constituent-based description of the wall mechanics. Using this model, a fit of the pressure–radius curve was then performed by using the experimental collagen recruitment distribution with the collagen elastic constant as a free fit parameter. The fit was good, but the value of the collagen elastic constant obtained was below values reported in the literature. A second fit of the pressure–radius curve was also performed, whereby the collagen distribution was left free to adapt while the collagen elastic constant was set to a physiological value. The differences between the experimental collagen engagement distribution and the distribution obtained when the collagen elastic constant was fixed were analyzed. Good qualitative agreement was found between the experimental distribution of collagen recruitment and the model. Some experimental limitations and modeling approximations remain. Nevertheless, experimental proof of progressive collagen recruitment was established, which validates the basic hypothesis of the model.

Inhibition of intimal hyperplasia after stenting by over-expression of p15: A member of the INK4 family of cyclin-dependent kinase inhibitors

We evaluated the role of p15Ink4, a member of the INK4 family of CDK inhibitors on vascular smooth muscle cells (VSMCs) proliferation, cell cycle progression and intimal hyperplasia after stenting. Aortic VSMCs transduced with either adenovirus encoding for p15Ink4 or β-galactosidase were assessed for DNA synthesis, cell cycle progression, and pRb phosphorylation. Rabbit carotid arteries were stented and treated with peri-adventitial delivery of saline or adenovirus encoding for p15Ink4 or β-galactosidase. p15Ink4 transgene and protein expression were evaluated at 24 h and 72 h, respectively. In-stent cell proliferation was evaluated by BrdU at day 7. Histomorphometric analysis of in-stent intimal hyperplasia was performed at 10weeks. Human p15Ink4 DNA was detected in transduced VSMCs at 24h. p15Ink4 over-expression reduced VSMCs DNA synthesis by 60%. Cell cycle progression was inhibited, with a 30% increase in G1 population accompanied by inhibition of pRb phosphorylation. Human p15Ink4 transgene was identified in transduced stented arteries but not in control arteries. p15Ink4 immunostaining was increased and cell proliferation significantly reduced by 50% in p15Ink4 transduced arteries. Intimal cross-sectional area (CSA) of p15Ink4-treated group was significantly lower than the β-gal treated and non-transduced groups (p=0.008). There were no differences in the intimal or medial inflammatory response between groups. p15Ink4 over-expression blocks cell cycle progression leading to inhibition of VSMCs proliferation. Peri-adventitial delivery of p15Ink4 significantly inhibits in-stent intimal hyperplasia.

Mechanisms underlying the diabetes-induced hyporeactivity of the rabbit carotid artery to atrial natriuretic peptide

Atrial natriuretic peptide (ANP) plays an important role in the pathophysiology of the vascular complications in diabetes. The working hypothesis was that diabetes might modify the vascular actions of ANP in isolated rabbit carotid arteries and the mechanisms involved in these actions. ANP (10 −12–10 −7 M) induced a relaxation of precontracted carotid arteries, which was lower in diabetic than in control rabbits. In arteries from both groups of animals, endothelium removal increased the ANP-induced relaxation. Isatin inhibited the relaxation to ANP both in arteries with and without endothelium. Carotid arteries from diabetic rabbits showed a decreased natriuretic peptide receptor (NPR)-A expression and an enhanced NPR-C expression. Inhibition of NO-synthesis did not modify ANP-induced relaxation in control rabbits but inhibited it in diabetic rabbits. In arteries with endothelium indomethacin enhanced the relaxation to ANP in control rabbits but did not modify it in diabetic rabbits. In endothelium-denuded arteries indomethacin inhibited the relaxation to ANP in both groups of animals. In KCl-depolarised arteries, relaxation to ANP was almost abolished both in control and diabetic rabbits. Tetraethylammonium inhibited the relaxation to ANP, and this inhibition was higher in diabetic than in control rabbits. These results suggest that diabetes produces hyporeactivity of the rabbit carotid artery to ANP by a mechanism that at least includes a reduced expression of NPR-A, an enhanced expression of NPR-C and a reduced participation of K +-channels. Furthermore, diabetes enhances endothelial NO release and diminishes the ratio thromboxane A 2/prostacyclin. This increase of vasodilators could result from compensatory mechanisms counteracting the arterial hyporeactivity to ANP.

Study of relationship between formation of internal carotid artery aneurysm and changes of vascular smooth muscle cells in rabbits

Objective To developmental changes in vascykar smooth muscle cells(VSMC)during abeyrtsm formation using an elastase-induced rabbit carotid artery aneurysm model. Methods Aneurysm was induced in carotid arteries of rabbits by exposure to elastase. Tissues from developing aneurysms were isolated at various time points for histological, immunohistochemical and RT-PCR analysis. Results During the aneurysm growth, the vascular media became thinner and elastic fibers became fragmented.The expression of smooth muscle marker SM22α-mRNA and cytoskeleton proteins (SM α-actin, β-Tubulin and Desmin) expression was decreased while platelet-derived growth factor (PDGF) was increased, which correlated with a remodeling of VSMC from contractiler to synthetic functions. Conclusion During the development of aneurysm, VSMC is remodeled from the contractile phenotype to a synthetic phenotype as a potential repair mechanism. Further studies may reveal the causative effects between these events. Key words: Aneurysm; Vascular smooth muscle cells; Phenotype; Cytoskeleton proteins

Delivery of TFPI-2 Using Ultrasound with a Microbubble Agent (SonoVue) Inhibits Intimal Hyperplasia after Balloon Injury in a Rabbit Carotid Artery Model

Here we report a new, simple and efficient method by using ultrasound and a microbubble agent (SonoVue) for delivering a gene to balloon-injured carotid arteries for restenosis prophylaxis. The tissue factor pathway inhibitor-2 (TFPI-2) has been shown to inhibit the postinjury intimae hyperplasia in atherosclerotic vessels. New Zealand white rabbits were divided into 4 groups with 14 in each, a treatment control for balloon injury, a gene vehicle control, a gene delivery of TFPI-2 without using ultrasound and a gene delivery of TFPI-2 using ultrasound. After four weeks, the injured artery neointimal proliferation was significantly lower in the TFPI-2 group with ultrasound than the control groups ( p < 0.01) according to the measurement of the mean luminal diameters by B-mode ultrasonography. The ratio of intimal/media area and the stenosis rate in the gene delivery facilitated by ultrasound were significantly lower than those of the nonultrasound gene delivering method ( p < 0.01). (E-mail: chenjuanlinda@gmail.com)

E0195 Research on the evaluation of OCT on atherosclerotic plaques of carotid artery in rabbits with insulin resistance

ObjectiveThe purpose was to analyse the feasibility and repeatability of OCT to evaluate atherosclerotic plaque diagnosed by pathologic examination of common carotid artery in rabbits with insulin resistance.MethodsThere were 26...

Vascular smooth muscle cell remodelling in elastase-induced aortic aneurysm

Objective — The objective of this study was to identify developmental changes in vascular smooth muscle cells (VSMC) during aneurysm formation using an elastase-induced rabbit carotid artery aneurysm model.Methods — Aneurysms were induced in carotid arteries of rabbits by exposure to elastase. Tissues from developing aneurysms were isolated at various time points for histological, immunohistochemical and RT-PCR analysis.Results — During aneurysm growth, the vascular media became thinner and elastic fibres became fragmented.The expression of smooth muscle marker SM22a and cytoskeleton proteins (SM a-actin, b-tubulin and desmin) expression was decreased while platelet-derived growth factor (PDGF) was increased, which correlated with a remodelling of VSMC from contractile to synthetic functions.Conclusion — During the development of aneurysm, despite the induction of apoptosis, VSMC undergoes a remodelling from a contractile phenotype to a synthetic phenotype as a potential repair mechanism. Further studies may reveal the causative effects between these events.

Detection and photodynamic therapy of inflamed atherosclerotic plaques in the carotid artery of rabbits

Photodynamic therapy (PDT) has been applied in the treatment of artery restenosis following balloon injury. This study aimed to detect the accumulation of 5-aminolevulinic acid (ALA)-derived protoporphyrin IX (PpIX) in inflamed atherosclerotic plaque in rabbit model and evaluate the efficacy of PDT. The inflamed atherosclerotic plaque in the common carotid artery was produced by combination of balloon denudation injury and high cholesterol diet. After intravenous administration of ALA, the fluorescence of PpIX in plaque was detected. At the peak time, the correlation between the fluorescence intensity of PpIX and the macrophage infiltration extent in plaque was analyzed. Subsequently, PDT (635 nm at 50 J/cm 2) on the atherosclerotic plaques ( n = 48) was performed and its effect was evaluated by histopathology and immunohistochemistry. The fluorescence intensity of PpIX in the plaque reached the peak 2 h after injection and was 12 times stronger than that of adjacent normal vessel segment, and has a positive correlation with the macrophage content ( r = 0.794, P < 0.001). Compared with the control group, the plaque area was reduced by 59% ( P < 0.001) at 4 week after PDT, the plaque macrophage content decreased by 56% at 1 week and 64% at 4 week respectively, the smooth muscle cells (SMCs) was depleted by 24% at 1 week ( P < 0.05) and collagen content increased by 44% at 4 week ( P < 0.05). It should be pointed out that the SMC content increased by 18% after PDT at 4 week compared with that at 1 week ( P < 0.05). Our study demonstrated that the ALA-derived PpIX can be detected to reflect the macrophage content in the plaque. ALA mediated PDT could reduce macrophage content and inhibit plaque progression, indicating a promising approach to treat inflamed atherosclerotic plaques.

Influence of adventitia injury-induced atherosclerosis on sympathetic nerve function in rabbits

Objective To evaluate the effect of adventitia injury on atherosclerosis(AS)development,norepinephrine content,and sympathetic nerve density in the carotid artery of rabbits,so as to analyze the effect of Tongxinluo(TXL) on AS and the possible mechanism.Methods Totally 96 male rabbits with left carotid adventitia removed were fed with high cholesterol diet and were divided into two groups randomly:one group was lavaged with TXL (TXL group) and the other with water (adventitia injury group).In each group the adventitia of left cervical artery was injured and the right one served as control.The bilateral carotid artery specimens and blood samples were collected 1 d,3 d,7 d,2 w,4 w,and 8 w after the operation.The norepinephrine contents in serum and carotid artery were determined by ELISA and the density of the sympathetic nerve was analyzed by immnohistochemical method.Results In the adventitia injury group adventitia injury aggravated AS in the left carotid artery compared with that in the right carotid artery;the area of atherosclerotic plaque was positively correlated with the nerve density(r=0.94,P0.05)and local norepinephrine content in the artery (r=0.90,P0.05).TXL significantly decreased the area of atherosclerotic plaque compared to the advetitia injury group (IMR[48±2]% vs [70±3]%,P0.01);besides,it also decreased the level of norepinephrine in the artery([83.76±3.3] ng/g vs [74.25±2.1] ng/g,P0.05)and the density of the sympathetic nerve(P0.05).Conclusion Adventitia injury can promote the development of AS in high-cholesterol fed animals,partially through promoting the disorder of local sympathetic function,and TXL can inhibit the adventitia injury-induced AS.

Lactoferricin B-derived peptides with inhibitory effects on ECE-dependent vasoconstriction

Endothelin-converting enzyme (ECE), a key peptidase in the endothelin (ET) system, cleaves inactive big ET-1 to produce active ET-1, which binds to ET A receptors to exert its vasoconstrictor and pressor effects. ECE inhibition could be beneficial in the treatment of hypertension. In this study, a set of eight lactoferricin B (LfcinB)-derived peptides, previously characterized in our laboratory as angiotensin-converting enzyme (ACE) inhibitory peptides, was examined for their inhibitory effects on ECE. In vitro inhibitory effects on ECE activity were assessed using both the synthetic fluorogenic peptide substrate V (FPS V) and the natural substrate big ET-1. To study vasoactive effects, an ex vivo functional assay was developed using isolated rabbit carotid artery segments. With FPS V, only four LfcinB-derived peptides induced inhibition of ECE activity, whereas the eight peptides showed ECE inhibitory effects with big ET-1 as substrate. Regarding the ex vivo assays, six LfcinB-derived peptides showed inhibition of big ET-1-induced, ECE-dependent vasoconstriction. A positive correlation between the inhibitory effects of LfcinB-derived peptides on ECE activity when using big ET-1 and the inhibitory effects on ECE-dependent vasoconstriction was shown. ECE-independent vasoconstriction induced by ET-1 was not affected, thus discarding effects of LfcinB-derived peptides on ET A receptors or intracellular signal transduction mechanisms. In conclusion, a combined in vitro and ex vivo method to assess the effects of potentially antihypertensive peptides on the ET system has been developed and applied to show the inhibitory effects on ECE-dependent vasoconstriction of six LfcinB-derived peptides, five of which were dual vasopeptidase (ACE/ECE) inhibitors.

The antithrombotic effect of a novel hirudin derivative after reconstruction of carotid artery in rabbits

Introduction Hirudin is a direct thrombin inhibitor that has potential mechanistic advantages over indirect inhibitors. Peptides containing the RGD motif competitively inhibit binding of fibrinogen to glycoprotein IIb/IIIa on platelets, thus inhibiting platelet aggregation. A novel hirudin derivative, recombinant RGD-hirudin (r-RGD-hirudin), was engineered by fusing the tripeptide RGD sequence to the native hirudin. We tested the antithrombotic effect of r-RGD-hirudin using a carotid artery reconstruction model in rabbits. Materials and methods A fusion gene encoding r-RGD-hirudin was constructed and expressed at high levels in Pichia pastoris. Following traumatic injury and anastomosis, 42 New Zealand White rabbits were randomized to receive normal saline, abciximab, wild-type hirudin, or r-RGD-hirudin. Fibrinogen concentration, aPTT, TT, PT, and PAGm were measured prior to and following the operation. Carotid angiography and pathological examination of the anastomotic site were performed to compare patency rates among the groups. Results The r-RGD-hirudin significantly prolonged aPTT, TT, PT and inhibited PAGm following carotid anastomosis in rabbits. The median dose of r-RGD-hirudin (0.5 mg/kg) had a therapeutic effect equal to that of wild-type hirudin (1.0 mg/kg) and higher than that of abciximab (0.2 mg/kg) with regard to patency rates. Conclusions Compared to wild-type hirudin or antiplatelet agent, the novel anticoagulant, r-RGD-hirudin was capable of inhibiting both thrombin activity and platelet aggregation, and was demonstrated to be effective in the prevention of thrombosis.

Bolus Delivery of Mesenchymal Stem Cells to Injured Vasculature in the Rabbit Carotid Artery Produces a Dysfunctional Endothelium

Endothelial dysfunction is an important factor in cardiovascular pathology. It has been suggested that pluripotent mesenchymal stem cells (MSCs) may contribute to repair of the endothelium through paracrine pathways. Enhanced re-endothelialization may be associated with a better outcome following angioplasty procedures. We examined the effect of the delivery of MSCs to a denuded vessel in vivo. The right carotid arteries of New Zealand white rabbits were denuded using an uninflated 3-French Fogarty balloon catheter. 1 x 10(5) MSCs in a bolus of 150 microL were then delivered intraluminally and allowed to dwell for 20 min. MSC engraftment was assessed using PKH-26 labeling and transduction with adenoviral reporter genes. Vessels were examined at 2 weeks for levels of endothelialization, as well as for neointimal hyperplasia and vasomotor function. Engraftment of MSCs was noted in the vessel wall following local arterial delivery. Endothelialization was improved following bolus MSC delivery at 2 weeks post-intervention. However, this endothelium is manifestly dysfunctional as indicated by a significant impairment in vasomotor activity and a significant increase in neointimal formation post-bolus delivery. Consistent with the formation of a dysfunctional endothelium, there was a higher rate of vessel occlusions in bolus-treated vessels due to not only predominately thrombosis but also neointimal hyperplasia. Our results suggest that naive MSCs delivered as a bolus to the occluded injured vascular segment generate dysfunctional endothelium presenting a risk of vessel occlusion. Such risks are important and need to be further assessed.

Atorvastatin Reduces Plaque Vulnerability in an Atherosclerotic Rabbit Model by Altering the 5-Lipoxygenase Pathway

Objective: The 5-lipoxygenase catalyzed formation of leukotriene lipid mediators is a mediator for inflammatory response in arteries. The present study investigated the relationship between atorvastatin and the 5-lipoxygenase pathway in an atherosclerotic rabbit model. Methods: Thirty male New Zealand White Rabbits were randomized into negative control, positive control and atorvastatin groups. At week 4, the rabbits were subjected to carotid balloon-dilation injury or carotid balloon-dilation injury, followed by treatment with atorvastatin. At week 12, all the animals were sacrificed. Plasma lipids, LTD₄, and 15-epi-lipoxin A₄ were measured using the enzymatic endpoint method and ELISA, respectively. RT-PCR was performed to detect the gene expression of 5-lipoxygenase-activating protein and cysLT1R in rabbit carotid arteries. Finally, histological analysis was used to evaluate the pathophysiological changes of rabbit carotid arteries. Results: The results showed atorvastatin markedly lowered serum lipids and LTD₄ levels compared with the control group. Similarly, mRNA expression of 5-lipoxygenase-activating protein and cysLT1R was significantly inhibited by atorvastatin. Decreased carotid plaque instability was evident in atorvastatin-treated animals, as demonstrated by a thickened elastic layer, less neointima hyperplasia and macrophage proliferation. Conclusions: Atorvastatin may stabilize carotid plaque by regulating the 5-lipoxygenase pathway in atherosclerotic rabbits and delay the progression of atherosclerosis by exerting anti-inflammatory effects.

Adenovirus-Mediated Overexpression of Glutathione-S-Transferase Mitigates Transplant Arteriosclerosis in Rabbit Carotid Allografts

Cardiac transplant arteriosclerosis or cardiac allograft vasculopathy remains the leading cause of graft failure and patient death in heart transplant recipients. Endothelial cell injury is crucial in the development of human atherosclerosis and may play a role in allograft vasculopathy. Glutathione-S-transferase (GST) is known to protect endothelial cells from damage by oxidants and toxins. However, the contribution of human GST A4-4 (hGSTA4-4) to vascular cell injury and consequent transplant arteriosclerosis is unknown. A recombinant adenoviral vector containing hGSTA4-4 gene was constructed and delivered to vascular endothelial cells in an in vivo rabbit carotid artery transplant model. Forty-five days after transplantation, allografts were harvested (n=28). Blood flow was measured by ultrasonography. In addition, grafts were analyzed by histology, morphometry, immunostaining, and western blot. The severity of arteriosclerosis in hGSTA4-4 transduced allografts was compared with control by measuring degree of stenosis by neointima. Decrease in blood flow in hGSTA4-4 transduced allografts was significantly less than control allografts, which also developed greater intimal thickening and stenosis than hGSTA4-4 transduced allografts in the proximal and distal regions of the graft. Leukocyte and macrophage infiltration was reduced in hGSTA4-4 transduced carotid arteries. Our data indicate that hGSTA4-4 overexpression protects the integrity of vessel wall from oxidative injury, and attenuates transplant arteriosclerosis.

Effects of nicardipine on collar-induced intimal thickening and vascular reactivity in the rabbit.

The effects of nicardipine treatment on collar-induced intimal thickening and on accompanying reactivity changes in rabbit carotid artery have been investigated. Treatment for three weeks with subcutaneous nicardipine (20 mgkg(-1) per day) significantly inhibited the intimal thickening caused by perivascular application of a silicone rubber collar. Potassium chloride (KCl), phenylephrine and 5-hydroxytryptamine (5-HT) induced concentration-dependent contractions in both sham-operated and collared arteries. Collar-induced attenuation of maximum KCl-, phenylephrine- and 5-HT-induced contraction was not affected by nicardipine. Collaring caused the means of pD2 values (the negative logarithm of EC50 values, 50% effective concentration) of 5-HT and phenylephrine to increase and decrease, respectively. Nicardipine did not affect the altered sensitivity to these agonists. Neither collar implantation nor nicardipine treatment altered the pD2 values for acetylcholine- and nitroglycerine-induced relaxations. These results demonstrate that nicardipine inhibits collar-induced intimal thickening in rabbit carotid artery without affecting the accompanying changes in vascular reactivity, indicating a possible lack of association between the development of intimal thickening and altered reactivity.

The role of endothelin receptor antagonism in collar-induced intimal thickening and vascular reactivity changes in rabbits

Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5 mg kg(-1) daily, s.c.), a non-selective ET(A)/ET(B) receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.

Delayed re-endothelialization with rapamycin-coated stents is rescued by the addition of a glycogen synthase kinase-3β inhibitor

Drug-eluting stents (DESs) reduce neointima area and in-stent restenosis but delay re-endothelialization. Recently, we demonstrated that pharmacological expansion and functional enhancement of endothelial progenitor cells (EPCs) can be achieved by treatment with a glycogen synthase kinase-3beta inhibitor (GSKi)-even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the alpha-4 integrin, ameliorated re-endothelialization, and reduced neointima formation in denuded murine arteries. Hence, we hypothesized that GSKi-coated stents (GSs) will enhance EPC adhesion and attenuate delayed vascular healing associated with rapamycin, a key DES agent. In vitro human EPCs adhered to GS with affinities that were 2x, 14x, and 13x greater than vehicle (VSs)-, rapamycin (RSs)-, and rapamycin plus GSKi (RGSs)-coated stents, respectively. Stents were inserted in rabbit carotid arteries, and at 14 days, neointima area was 45 and 49% lower in GSs compared with bare metal stents (BMSs) and VSs. Moreover, RSs had a 47% larger neointima area than GSs, but RGSs reduced neointima area to a level comparable to GSs. Seven days after stenting, GSs displayed re-endothelialization that was 40, 33, and 42% greater than BMSs, VSs, and RSs, respectively. Moreover, RGSs had 41% more re-endothelialization than RSs. At 14 days, the 7-day re-endothelialization patterns persisted. GSKi efficiently ameliorates the vascular response to stent implantation and has an important redeeming effect on the deleterious endothelial effects of rapamycin-coated stents.

Intravascular tissue reactions induced by various types of bioabsorbable polymeric materials: correlation between the degradation profiles and corresponding tissue reactions

IntroductionSeveral different bioabsorbable polymeric coil materials are currently used with the goal of improving treatment outcomes of endovascular embolization of intracranial aneurysms. However, little is known about the correlation between polymer degradation profiles and concomitant tissue responses in a blood vessel. The authors describe in vitro degradation characteristics of nine different polymeric materials and their corresponding tissue responses induced in rabbit carotid arteries.Methods Mass loss and molecular weight loss of nine commercially available bioabsorbable sutures were evaluated in vitro up to16 weeks. The same nine materials, as well as platinum coils, were implanted into blind-end carotid arteries (n = 44) in rabbits, and their tissue reactions were evaluated histologically 14 days after the implantation.ResultsFive of the nine polymers elicited moderate to strong tissue reactions relative to the remaining materials. While polymer mass loss did not correlate with their histologic findings, polymers that showed a faster rate of molecular weight loss had a tendency to present more active tissue reactions such as strong fibrocellular response around the implanted material with a moderate inflammatory cell infiltration. Maxon exhibited the fastest rate of molecular weight loss and poly-l-lactic acid the slowest.ConclusionsThe rate of molecular weight loss may be an important factor that is associated with the degree of bioactivity when bioabsorbable polymers are implanted into blood vessels. For further quantitative analysis, additional experiments utilizing established aneurysm models need to be conducted.