Effect of resveratrol on intimal hyperplasia after endothelial denudation in an experimental rabbit model

The ability of resveratrol to inhibit vascular intimal thickening was tested in an experimental model in which endothelial denudation was performed in the normal rabbit iliac artery. Resveratrol (2 approximately 4mg/ kg/d) was administered intragastrically for 5 weeks beginning 1 week before denudation. At the higher concentration of resveratrol, the intimal hyperplasia of injured vascular wall was effectively inhibited; the intimal proliferation index also was significantly less than that in the untreated control group (0.28 +/- 0.07 vs 0.41 +/- 0.13, respectively, p<0.01); the relative luminal area increased from 0.38 +/- 0.06 in the untreated control group to 0.53 +/- 0.10 in the resveratrol treatment group (p < 0.001); and the count of smooth muscle cells in the thickened intima was statistically significantly reduced in the high dose resveratrol treatment group than that in the untreated group (1,115 +/- 510 vs 1,796 +/- 963, respectively, p < 0.05). Resveratrol added to the culture media of cultured rabbit vascular smooth muscle cells inhibited DNA synthesis in a dose-dependent manner. These results showing that resveratrol is capable of inhibiting intimal hyperplasia of injured artery raise the possibility that this polyphenol might have clinical potential in prevention and treatment of restenosis after angioplasty.     

Multiscale bio-chemo-mechanical model of intimal hyperplasia

We consider a computational multiscale framework of a bio-chemo-mechanical model for intimal hyperplasia. With respect to existing models, we investigate the interactions between hemodynamics, cellular dynamics and biochemistry on the development of the pathology. Within the arterial wall, we propose a mathematical model consisting of kinetic differential equations for key vascular cell types, collagen and growth factors. The luminal hemodynamics is modeled with the Navier–Stokes equations. Coupling hypothesis among time and space scales are proposed to build a tractable modeling of such a complex multifactorial and multiscale pathology. A one-dimensional numerical test-case is presented for validation by comparing the results of the framework with experiments at short and long timescales. Our model permits to capture many cellular phenomena which have a central role in the physiopathology of intimal hyperplasia. Results are quantitatively and qualitatively consistent with experimental findings at both short and long timescales.

     

An agent-based model of vibration-induced intimal hyperplasia

Biomechanics and Modeling in Mechanobiology - Acute exposure to hand-arm transmitted vibrations (HAVs) may decrease the wall shear stress (WSS) exerted by the blood flow on the arterial...     

Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasia.

We previously reported that heparin inhibits the proliferation of fibroblasts and vascular smooth muscle cells (SMC), in part, by binding to and increasing the antiproliferative activity of transforming growth factor-beta 1 (TGF-beta 1). We now report that certain other polyanions which are structurally distinct from heparin, such as fucoidan and polyinosinic acid, are more avid ligands for TGF-beta 1 and more potent antiproliferative agents than heparin. Fucoidan possessed more potent antiproliferative activity than heparin against rat and bovine aortic SMC in vitro, though possessing much lower anticoagulant activity than heparin. Furthermore, fucoidan suppressed in vivo intimal hyperplasia when continuously infused into rats subjected to balloon-catheter injury. Unlike heparin, which also suppressed intimal hyperplasia, fucoidan did not cause systemic anticoagulation. Thus, fucoidan may be useful as a non-anticoagulant inhibitor of post-angioplasty intimal hyperplasia.     

Trophic factor supplemented UW solution reduces intimal hyperplasia in the rat aortic transplant model

BACKGROUND: Chronic allograft nephropathy (CAN) is associated with delayed graft function, cold ischemic injury, and is an important cause of premature graft loss. A characteristic vascular lesion of CAN is intimal hyperplasia (IH). The goal of this study was to evaluate the effect of cold storage in University of Wisconsin solution supplemented with trophic factors (UW-TF) on IH in rat aortic isograft (IG) and allograft (AG) models. METHODS: F344 --> F344 and Lewis --> F344 orthotopic abdominal aortic transplants were performed after 48 h of cold storage in either UW or UW-TF solution with and without immunosuppression. RESULTS: Significant reduction in IH was observed when IG were stored in UW-TF solution compared to UW solution. A significant reduction in intimal inflammation was observed in UW-TF stored, nonimmunosuppressed AG. In immunosuppressed recipients, AG stored in UW-TF solution evidenced significantly less IH compared to those stored in UW alone. CONCLUSIONS: UW-TF solution decreased IH in both alloindependent and dependent models.     

Lack of intimal hyperplasia response in an experimental model of non-endothelial vascular wall damage.

The endothelial and medial layers are generally presumed to play an important role in the appearance and development of intimal hyperplasia. We have carried out a short-, media- and long-term study of the morphological changes taking place in the common iliac artery of rats after surgical removal of the adventitial layer. Our aim has been to assess the likely role played by this layer in the development of intimal hyperplasia. Our results show recurrent periods of cellular desquamation and almost complete absence of hyperplastic response during the first two months. After three months three is a slow process of endothelialization which is completed by the 6th month and persists one year after adventitial resection. Thus, adventitial resection seems to cause instability at the subendothelial bed level, not allowing the junction and embedding of endothelial cells nor the development of intimal hyperplasia. This lack of hyperplasia might also result from the fact that the endothelial desquamation process does not involve cellular rupture, which would prevent mitogenic-factor release. After morphological repair of the endothelium, a slow morphofunctional recovery of the artery takes place.     

Hydroxyapatite electret accelerates reendothelialization and attenuates intimal hyperplasia occurring after endothelial removal of the rabbit carotid artery

The present experiments were designed to investigate whether electrically polarized hydroxyapatite (HA electret) modifies reendothelialization and intimal hyperplasia occurring after endothelial removal of the rabbit carotid artery. Both HA electret and non-polarized HA, which served as a control, had been powdered and mixed with agarose gel. One of the two was applied around the external surface of the carotid artery. Histological analyses revealed that HA electret but not control HA significantly inhibited intimal hyperplasia. The number of Ki67-positive cells detectable in the intimal layer was significantly fewer in the HA electret group. In the HA electret group, abundant TUNEL-positive cells were detected in the media. The number of CD31-positive cells detected on the luminal surface was significantly higher in the HA electret group. Endothelium- and nitric oxide (NO)-dependent relaxation in response to carbachol was significantly improved only in the HA electret group. In conclusion, this is the first report demonstrating that HA electret significantly improved intimal hyperplasia by accelerating the regeneration of functioning endothelial cells and enhancing the apoptosis of medial smooth muscle cells.     

The role of intimal hyperplasia in arterial spasm.

It has been postulated that even moderate spasm in an artery with intimal hyperplasia can produce organ hypoxia because there is an excessive reduction in the diameter of the lumen. To test this hypothesis we created intimal hyperplasia in one femoral artery in five pigs and then induced arterial spasm by administering ergonovine maleate. Arterial spasm did not produce a greater reduction in the luminal diameter of the femoral artery with intimal hyperplasia than it did in the normal femoral artery. Until further evidence appears this hypothesis must be viewed with caution.     

Nitric oxide and nitrite-based therapeutic opportunities in intimal hyperplasia

Vascular intimal hyperplasia (IH) limits the long term efficacy of current surgical and percutaneous therapies for atherosclerotic disease. There are extensive changes in gene expression and cell signaling in response to vascular therapies, including changes in nitric oxide (NO) signaling. NO is well recognized for its vasoregulatory properties and has been investigated as a therapeutic treatment for its vasoprotective abilities. The circulating molecules nitrite (NO(2)(-)) and nitrate (NO(3)(-)), once thought to be stable products of NO metabolism, are now recognized as important circulating reservoirs of NO and represent a complementary source of NO in contrast to the classic L-arginine-NO-synthase pathway. Here we review the background of IH, its relationship with the NO and nitrite/nitrate pathways, and current and future therapeutic opportunities for these molecules.     

Catheter-mediated delivery of adenoviral vectors expressing beta-adrenergic receptor kinase C-terminus inhibits intimal hyperplasia and luminal stenosis in rabbit iliac arteries

BACKGROUND: Previous studies have shown that incubation of balloon-injured rat carotid arteries with adenoviral vectors encoding the carboxyl terminus of the beta-adrenergic receptor kinase (Ad2/betaARKct) for 30 min reduces neointima formation. However, it is unclear whether this beneficial effect of betaARKct could be achieved using a catheter-based vector delivery system and whether the observed inhibition of neointima formation translated into a reduction of vessel stenosis. METHODS: In this study, Ad2/betaARKct was infused into the balloon-injured site of rabbit iliac arteries using a porous infusion catheter over 2 min. Twenty-eight days after gene transfer, angiographic and histological assessments were performed. RESULTS: Angiographic and histological assessments indicate significant (p < 0.05) inhibition of iliac artery neointima formation and lumen stenosis by Ad2/betaARKct. Our studies demonstrate that an inhibitory effect of Ad2/betaARKct on neointima formation is achievable using a catheter-based vector delivery system and that the inhibition of neointima formation translates into a gain in the vessel minimal luminal diameter. The extent of inhibition (35%) was comparable to that observed with adenoviral-mediated expression of thymidine kinase plus ganciclovir treatment, a cytotoxic gene therapy approach for restenosis. CONCLUSIONS: These results suggest that adenoviral-mediated gene transfer of betaARKct is a clinically viable cytostatic gene therapy strategy for the treatment of restenosis.     

Some characteristics of intimal folds in the rabbit aorta

A stereomicroscopic study of fresh rabbit aorta has shown that the intimal folds form a special pattern which reappears when the aorta is relaxed after stretching. The pattern of intimal folds seems to be adapted to and may be the result of continuously repeated movements of the vessel wall. This supports the view hat intimal folds are present in vivo.     

Intramuscular gene transfer of FGF-2 attenuates endothelial dysfunction and inhibits intimal hyperplasia of vein grafts in poor-runoff limbs of rabbit

We previously demonstrated that sustained disturbance of endothelium-dependent vasorelaxation and poor distal runoff in ischemic limbs were critical factors affecting the neointimal development of autologous vein grafts (VGs). Also, we recently showed the superior therapeutic potential of basic fibroblast growth factor (bFGF/FGF-2) boosted by the recombinant Sendai virus (SeV) for severe limb ischemia compared with that of vascular endothelial growth factor. Here, the effect of FGF-2 on neointimal hyperplasia of VGs was examined in a rabbit model of poor-runoff limbs. Two weeks after initial surgery for the induction of poor-runoff, SeV-expressing human FGF-2 (SeV-hFGF2) or that encoding firefly luciferase (109 plaque-forming units/head) was injected into the thigh and calf muscle. At that time, the femoral vein was implanted in the femoral artery in an end-to-end manner in some groups. FGF-2 gene-transferred limbs demonstrated significantly increased blood flow assessed not only by laser Doppler flow image but also by ultrasonic transit-time flowmeter (USTF). USTF also showed a significant increase in the blood flow ratio of the deep femoral artery to external iliac artery, indicating that collateral flow was significantly restored in the thigh muscles (P < 0.01). Reduction of neointimal hyperplasia was also observed in the VGs treated by SeV-hFGF2; these grafts demonstrated significant restoration of endothelium-dependent vasorelaxation. These findings thus extend the indications of therapeutic angiogenesis using SeV-hFGF2 to include not only limb salvage but also prevention of late graft failure.     

Protandim attenuates intimal hyperplasia in human saphenous veins cultured ex vivo via a catalase-dependent pathway

Human saphenous veins (HSVs) are widely used for bypass grafts despite their relatively low long-term patency. To evaluate the role of reactive oxygen species (ROS) signaling in intima hyperplasia (IH), an early stage pathology of vein-graft disease, and to explore the potential therapeutic effects of up-regulating endogenous antioxidant enzymes, we studied segments of HSV cultured ex vivo in an established ex vivo model of HSV IH. Results showed that HSV cultured ex vivo exhibit an ~ 3-fold increase in proliferation and ~ 3.6-fold increase in intimal area relative to freshly isolated HSV. Treatment of HSV during culture with Protandim, a nutritional supplement known to activate Nrf2 and increase the expression of antioxidant enzymes in several in vitro and in vivo models, blocks IH and reduces cellular proliferation to that of freshly isolated HSV. Protandim treatment increased the activity of SOD, HO-1, and catalase 3-, 7-, and 12-fold, respectively, and decreased the levels of superoxide (O₂^??) and the lipid peroxidation product 4-HNE. Blocking catalase activity by cotreating with 3-amino-1,2,4-triazole abrogated the protective effect of Protandim on IH and proliferation. In conclusion, these results suggest that ROS-sensitive signaling mediates the observed IH in cultured HSV and that up-regulation of endogenous antioxidant enzymes can have a protective effect.     

<Emphasis Type="Italic">Chlamydia pneumoniae</Emphasis> aggravates vein graft intimal hyperplasia in a rat model

Background  

Along with angioplasty, autologus vein grafts are commonly used for artery bypass grafting in patients with advanced arterial stenosis and drug-resistant angina pectoris. Although initially a successful procedure, long-term functionality is limited due to proliferation and migration of smooth muscle cells. Like in atherosclerosis, common chronic infections caused by viruses and bacteria may contribute to this process of vein graft failure. Here we investigated the possible role of Chlamydia pneumoniae (Cpn) in the pathogenesis of venous graft failure in an experimental animal model. In 2 groups (n = 10 rats/group), an epigastric vein-to-common femoral artery interposition graft was placed. Immediately thereafter, rats were infected with Cpn (5*10⁸ IFU) or injected with control solutions. Rats were sacrificed three weeks after surgery and the grafts were harvested for morphometrical and immunohistochemical analysis.