Ginsenoside Rg1 prevents vascular intimal hyperplasia involved by SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in a rat balloon injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Mey. is a traditional tonic that has been used for thousands of years, and has positive effects on vascular diseases. Ginsenoside Rg1 (GS-Rg1) is one of the active ingredients of Panax ginseng C. A. Mey. and has been shown to have beneficial effects against ischemia/reperfusion injury. Our previously study has found that GS-Rg1 can mobilize bone marrow stem cells and inhibit vascular smooth muscle proliferation and phenotype transformation. However, pharmacological effects and mechanism of GS-Rg1 in inhibiting intimal hyperplasia is still unknown. AIM OF THE STUDY: This study was aimed to investigate whether GS-Rg1 prevented vascular intimal hyperplasia, and the involvement of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1 axes. MATERIALS AND METHODS: Rats were operated with carotid artery balloon injury. The treatment groups were injected with 4, 8 and 16 mg/kg of GS-Rg1 for 14 days. The degree of intimal hyperplasia was evaluated by histopathological examination. The expression of α-SMA (α-smooth muscle actin) and CD133 were detected by double-label immunofluorescence. Serum levels of SDF-1α, SCF and soluble FKN (sFKN) were detected by enzyme linked immunosorbent assay (ELISA). The protein expressions of SCF, SDF-1α and FKN, as well as the receptors c-kit, CXC chemokine receptor type 4 (CXCR4) and CX3C chemokine receptor type 1 (CX3CR1) were detected by immunochemistry. RESULTS: GS-Rg1 reduced intimal hyperplasia by evidence of the values of NIA, the ratio of NIA/MA, and the ratio of NIA/IELA and the ratio of NIA/LA, especially in 16 mg/kg group. Furthermore, GS-Rg1 8 mg/kg group and 16 mg/kg group decreased the protein expressions of the SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in neointima, meanwhile GS-Rg1 8 mg/kg group and 16 mg/kg group also attenuated the expressions of SDF-1α, SCF and sFKN in serum. In addition, the expression of α-SMA and CD133 marked smooth muscle progenitor cells (SMPCs) was decreased after GS-Rg1 treatment. CONCLUSIONS: GS-Rg1 has a positive effect on inhibiting vascular intimal hyperplasia, and the underlying mechanism is related to inhibitory expression of SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes.

Dietary supplementation with Zyflamend poly-herbal extracts and fish oil inhibits intimal hyperplasia development following vascular intervention.

The polyherbal blend Zyflamend™ has been shown to have anti-inflammatory properties and attenuate inflammatory-modulated pathologies. Fish oils have also been shown to have cardioprotective properties. However, the beneficial effects of their combination have not been investigated. Intimal hyperplasia (IH), a pathological remodeling response of a vessel to injury, is heavily regulated by an immune-mediated reaction. The objective of this study was to determine if dietary supplementation with Zyflamend and/or Wholemega could affect inflammatory-dependent vascular remodeling mechanisms when provided at human equivalent doses. Based on their anti-inflammatory properties and protective benefits demonstrated in previous pre-clinical studies, we hypothesized administration of these supplements would prevent IH in an animal model of vascular injury. The diets of aged male rats were supplemented with human equivalent doses of Zyflamend (Zyf) and/or Wholemega (WMega) or placebo (Plac) for 1wk prior to balloon angioplasty (BA)-induced injury of the left carotid artery. At 28d post-injury morphometric analysis of carotid tissue revealed IH was decreased in Zyf + WMega animals compared to placebo, while Zyf or WMega independently had no significant effect. Serum cytokine screening indicated injury-induced interleukin family isoforms, interferon-γ, and macrophage inflammatory proteins were downregulated by Zyf + WMega. Immunohistochemical staining for monocyte/macrophage phenotypic markers revealed that while overall monocyte/macrophage vessel infiltration was not affected, Zyf + WMega limited the alternative differentiation of M2 macrophages and reduced the presence of myofibroblasts in the injured vessel wall. In summary, dietary supplementation with Zyf + WMega attenuated the acute inflammatory response following vascular injury and inhibited IH development in vivo.

Ginsenoside Re inhibits vascular neointimal hyperplasia in balloon-injured carotid arteries through activating the eNOS/NO/cGMP pathway in rats.

Ginsenoside Re (GS-Re) is one of the main ingredients of ginseng, a widely known Chinese traditional medicine, and has a variety of beneficial effects, including vasorelaxation, antioxidative, anti-inflammatory, and anticancer properties. The aims of the present study were to observe the effect of GS-Re on balloon injury-induced neointimal hyperplasia in the arteries and to investigate the mechanisms underlying this effect. A rat vascular neointimal hyperplasia model was generated by rubbing the endothelium of the common carotid artery (CCA) with a balloon, and GS-Re (12.5, 25 or 50 mg/kg/d) were subsequently continuously administered to the rats by gavage for 14 days. After GS-Re treatment, the vessel lumen of injured vessels showed significant increases in the GS-Re 25.0 and 50.0 mg/kg/d (intermediate- and high-dose) groups according to H.E. staining. Additionally, a reduced percentage of proliferating cell nuclear antigen (PCNA)-positive cells and an increased number of SM α-actin-positive cells were detected, and the levels of NO, cyclic guanosine monophosphate (cGMP), and eNOS mRNA as well as the phos-eNOSser1177/eNOS protein ratio were obviously upregulated in the intermediate- and high-dose groups. Moreover, the promotive effects of GS-Re on NO and eNOS expression were blocked by L-NAME treatment to different degrees. These results suggested that GS-Re can suppress balloon injury-induced vascular neointimal hyperplasia by inhibiting VSMC proliferation, which is closely related to the activation of the eNOS/NO/cGMP pathway.

"Mixed" trauma to the carotid artery in a mixed martial arts injury - A case report and review of the literature.

We present the case of a mixed martial arts (MMA) cage fighter who presented to the emergency department with a right sided common carotid artery pseudoaneurysm as a result of a neck trauma at an MMA event. We discuss the management of blunt force neck trauma, differential diagnosis, imaging findings and review the literature on blunt cerebrovascular injury following blunt force injury to the neck.

Internal Carotid Artery Strains During High-Speed, Low-Amplitude Spinal Manipulations of the Neck.

OBJECTIVE: The primary objective of this study was to quantify the strains applied to the internal carotid artery (ICA) during neck spinal manipulative treatments and range of motion (ROM)/diagnostic testing of the head and neck. METHODS: Strains of the ICA (n = 12) were measured in 6 fresh, unembalmed cadaveric specimens using sonomicrometry. Peak and average strains of the ICA obtained during cervical spinal manipulations given by experienced doctors of chiropractic were compared with the corresponding strains obtained during ROM and diagnostic testing of the head and neck. RESULTS: Peak and average strains of the ICA for cervical spinal manipulative treatments were significantly smaller (P < .001) than the corresponding strains obtained for the ROM and diagnostic testing. All strains during ROM and treatment testing were dramatically smaller than the initial failure strains of the ICA. CONCLUSIONS: This study showed that maximal ICA strains imparted by cervical spinal manipulative treatments were well within the normal ROM. Chiropractic manipulation of the neck did not cause strains to the ICA in excess of those experienced during normal everyday movements. Therefore, cervical spinal manipulative therapy as performed by the trained clinicians in this study, did not appear to place undue strain on the ICA and thus does not seem to be a factor in ICA injuries.

[A case of blunt common carotid artery injury following minor trauma].

Cervical major blood vessel injuries often produce acute ingravescence of the circulatory dynamics. Therefore, if immediate treatment is not given, fatal complications can occur, resulting in death. Common carotid artery (CCA) injuries in particular are often associated with fatal outcomes. Moreover, most CCA injuries with hemorrhage producing hematoma are the result penetrating trauma, and there are few reports of blunt injuries. We report herein on a case of blunt CCA injury producing acute hematoma due to minor trauma. A 35-year-old man who was gently punched on his jaw when he was training with his child visited emergency room in our hospital complaining of swelling and pain of his neck soon after that. When we examined his neck, the larynx was displaced to the left by right neck swelling. Flexible transnasal laryngoscopic examination revealed constriction of the suffocating airway by a hematoma, so an emergency tracheotomy was performed. Enhanced CT of the neck showed active bleeding, so emergency surgical removal of the hematoma and hemostasis was carried out. We found a laceration (approximately 2 cm) of the CCA, and arrested hemorrhage with sutures. No postoperative neurologic deficit occurred. His postoperative course was good, and discharged 22 days after the operation.

Laser-induced carotid artery injury model in the rat for therapeutic agent screening.

The aims of this study were to establish a rat model of carotid artery injury and to evaluate its suitability for evaluating therapeutic agents active against endothelial proliferation. Wistar-Kyoto rats were injected intravenously with the photochemically reactive dyes rose bengal or Evans blue, and the carotid artery was then focally irradiated with laser light of the appropriate wavelength. Histological sections of the carotid artery were analyzed to determine the appropriate parameters for this model. Ferulic acid was used to assess the suitability of this model for drug screening. No animal died as a result of the photochemical treatment. Endothelial proliferation in the carotid artery was observed in rats injected with rose Bengal and exposed to green laser light. Ferulic acid (400 mg/kg per day) significantly (p<0.05) reduced endothelial proliferation in the carotid artery 28 days after injury in dye-treated animals compared with vehicle-treated animals. This simple experimental rat model is suitable for studying factors inhibiting endothelial thickening after vessel damage and for developing therapeutic strategies active against endothelial proliferation.

Inhibitory effect of n-butylidenephthalide on neointimal hyperplasia in balloon injured rat carotid artery.

This investigation was designed to determine the inhibitory effects and mechanisms of n-butylidenephthalide (BP) from Angelica sinensis on smooth muscle cell (SMC) proliferation in vitro and in balloon injured rat carotid artery. Treatment of cultured rat aorta SMC-derived A7r5 cells with 25-100 µg/mL BP significantly inhibited the proliferation and arrested the cell cycle in G(0)/G(1) phase. BP induced the expression and migration of Nur77 from the nucleus to the cytoplasm. Among signal pathways, JNK and p38 MAPK were phosphorylated after BP treatment. In vivo, the neointimal area of common carotid artery 2 weeks after balloon injury reduced significantly in Sprague-Dawley rats treated with 150-300 mg/kg BP compared with the control. The proliferative activity indicated by immunohistochemical detection of Ki-67 positive cells in the neointima was significantly decreased in the 60-300 mg/kg BP treatment groups. The apoptotic activity indicated by cleaved caspase-3 positive cells and Nur77 positive cells in the neointima was significantly increased in rats treated with 60-300 mg/kg BP. This study demonstrated BP inhibited neointimal hyperplasia in balloon injured rat carotid artery due to its dual effects of proliferative inhibition and apoptotic induction on SMCs. Up-regulation of Nur77 gene may partly explain the antihyperplasia activity of BP on the neointima.

Effects of isosorbide mononitrate on the restoration of injured artery in mice in vivo.

The pharmacological basis of isosorbide mononitrate (ISMN), a widely used drug for cardiovascular diseases, is that it is metabolized to nitric oxide (NO). However, NO is a double-edged sword that results in either beneficial or detrimental effect. Vascular injury is the common consequence of many cardiovascular diseases, but it is not determined whether ISMN influences the restoration of injured artery in vivo. Carotid artery injury was induced by electric stimulation in mice. Vasoconstriction and endothelium-dependent and -independent relaxation were recorded by a multichannel acquisition and analysis system. ISMN (10 mg/kg, p.o.) treatment for 1 week and 1 month had no effect on reendothelialization, histology and function of carotid artery injured by electric stimulation. L-arginine (500 mg/kg, p.o.) and Nomega-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg, p.o.) treatment for 1 week did not affect the reendothelialization process, but L-NAME treatment induced neointimal hyperplasia and inhibited endothelium-dependent relaxation in electrically injured artery. These results suggest that supplement of exogenous or endogenous NO has no effect on the restoration of injured artery, but inhibition of endogenous NO induces neointimal hyperplasia in injured artery. ISMN treatment does not affect the restoration of injured artery.

Ginsenoside Rb1 attenuates homocysteine-augmented guidewire injury-induced intimal hyperplasia in mice.

BACKGROUND: Intimal hyperplasia (IH) is the primary cause for post-angioplasty restenosis. The purpose of this study is to investigate the effects of homocysteine (Hcy) and ginsenoside Rb1 (Rb1) on IH using a guidewire injury animal model. METHODS: In 12-wk-old C57BL/6J mice, the left common carotid artery (CCA) was denudated with a guidewire and the right CCA was used as the uninjured control. They were treated with saline (NS), Hcy, Rb1, or Hcy + Rb1 for 4 wk prior to sacrifice. Animals were sacrificed at 4, 6, or 8 wk. Both CCAs were harvested and intimal-medium thickness (IMT) ratios were calculated. Local macrophage distribution was also studied. RESULTS: Histology analyses demonstrated consistent internal elastic lamina disruption and focal IH in the injured CCA segments. The degree of IH correlated to the lengths of time following injury. Hcy treated group had significant increase in IMT compared with the NS group (P < 0.05), while Rb1 group was similar to the NS group. In addition, Hcy + Rb1 group showed significant improvement in IMT compared with Hcy group (P < 0.01). Furthermore, Hcy significantly increased local macrophage content as compared with either lesion alone or Rb1 treated animals. CONCLUSIONS: Our study showed that Hcy increased the degree of IH and macrophage content in the injured CCA and that Rb1 attenuated these adverse effects. These changes might be mediated through antioxidative effects of Rb1. Our data suggests a potential clinical application of ginseng in controlling Hcy-related vascular injuries.

[Pseudoaneurysm of the internal carotid artery following a tonsil biopsy: endovascular repair with covered stent]. / Tonsil biyopsisine bagli gelisen internal karotis arter psödoanevrizmasi: endovasküler kapli stent ile onarim.

Evaluation and management of peritonsillar masses require specific attention because of their relationship to vital neighboring anatomical structures. A 57-year-old woman developed pseudoaneurysm of the internal carotid artery following a biopsy taken at another center from a mass in the left tonsillar region. She was treated by a multidisciplinary approach and an endovascular covered stent was implanted under local anesthesia in the left internal carotid artery. No recurrence was detected in the neck and the patient was asymptomatic in the postoperative second year.

Iatrogenic carotid artery injury in neurosurgery.

Iatrogenic carotid artery injury (CAI) results from various neurosurgical procedures. A review of the literature was conducted to provide an update on the management of this potentially devastating complication. Iatrogenic CAIs are categorized according to each diagnostic or therapeutic procedure responsible for the injury, i.e., anterior cervical spine surgery, central venous catheterization, chemical substances, chiropractic manipulation, diagnostic cerebral angiography, middle-ear surgery, percutaneous procedures for trigeminal neuralgia, radiation therapy, skull-base surgery, tracheostomy, and transsphenoidal surgery. The incidence, mechanisms of injury, diagnostic imaging modalities, and reparative procedures are discussed for each procedure. Iatrogenic CAI may be more prevalent than had previously been thought, mostly because of a heightened awareness on the part of physicians and the earlier detection of asymptomatic patients owing to sophisticated and less-invasive imaging modalities. Prevention is the best treatment for every iatrogenic injury, and it is expected that further accumulation of experience with and knowledge of iatrogenic CAI will result in further reduction of this complication. Although some CAIs, such as radiation-induced carotid artery stenosis, may not be preventable, earlier intervention before the patient becomes symptomatic may favorably alter the prognosis. Following the rapid development of endovascular techniques in recent years, surgically inaccessible lesions can be treated in a more reliable and safe manner than before.

Inhibition of vascular smooth muscle cell proliferation and neointimal formation in injured arteries by a novel, oral mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) are rapidly induced after arterial injury in different animal models. However, their precise role in vascular smooth muscle cell (VSMC) proliferation and neointimal formation in vivo remains to be determined. METHODS AND RESULTS: We investigated the properties of a novel, selective inhibitor of the upstream kinase, MAPK/extracellular signal-regulated kinase, that is orally active (PD0185625). In vitro, PD0185625 was shown to abrogate p44/p42 MAPK activation in VSMCs after serum stimulation. This was associated with a dose-dependent inhibition of VSMC proliferation. In vivo, PD0185625 was administered orally to rats (200 mg x kg(-1) x d(-1)) beginning 2 days before balloon injury of the left carotid artery and for 2 weeks thereafter. Treatment with PD0185625 led to nearly complete inhibition of p44/p42 MAPK activation after balloon injury. This resulted in a significant decrease in VSMC proliferation (BrdU incorporation) at day 7 after injury. Moreover, neointimal formation was significantly reduced in PD0185625-treated animals at 14 and 28 days after arterial injury. We found that PD0185625 did not increase the rate of apoptotic cell death but prevented cell cycle progression and induced a G1 block. CONCLUSIONS: PD0185625 reduced neointimal formation after arterial injury. The mechanism involved inhibition of VSMC proliferation via a G1 block of the cell cycle. Orally active selective MAPK inhibitors could represent a novel therapeutic approach for vascular diseases.

[Experimental study on preventive effect of Radix Paeoniae Rubra to restenosis after carotid balloon injury in high fat-diet rabbits].

OBJECTIVE: To observe the preventive effect of Radix Paeoniae Rubra (RPR) to restenosis after carotid balloon injury in rabbits. METHODS: The rabbit model of carotid balloon injury was established adopting Clowes method, and treated with extract of RPR. Component of new genesic intima and expression of proliferating cell nuclear antigen (PCNA) and macrophage was determined by immunochemical stain. The collagen of type I was detected by special staining for blood vessels and the area of new genesic intima was measured by image assay system. RESULTS: RPR could remarkably decreased the PCNA positive expression and inhibit the proliferation of collagen type I and reduce the generating of new intima. CONCLUSION: RPR has significant preventive effect on the restenosis after carotid ballon injury in high fat-diet induced atherosclerotic rabbits.

Spinal manipulative therapy is an independent risk factor for vertebral artery dissection.

OBJECTIVE: To determine whether spinal manipulative therapy (SMT) is an independent risk factor for cervical artery dissection. METHODS: Using a nested case-control design, the authors reviewed all patients under age 60 with cervical arterial dissection (n = 151) and ischemic stroke or TIA from between 1995 and 2000 at two academic stroke centers. Controls (n = 306) were selected to match cases by sex and within age strata. Cases and controls were solicited by mail, and respondents were interviewed using a structured questionnaire. The medical records of interviewed patients were reviewed by two blinded neurologists to confirm that the patient had stroke or TIA and to determine whether there was evidence of arterial dissection. RESULTS: After interview and blinded chart review, 51 patients with dissection (mean age 41 +/- 10 years; 59% female) and 100 control patients (44 +/- 9 years; 58% female) were studied. In univariate analysis, patients with dissection were more likely to have had SMT within 30 days (14% vs 3%, p = 0.032), to have had neck or head pain preceding stroke or TIA (76% vs 40%, p < 0.001), and to be current consumers of alcohol (76% vs 57%, p = 0.021). In multivariate analysis, vertebral artery dissections were independently associated with SMT within 30 days (OR 6.62, 95% CI 1.4 to 30) and pain before stroke/TIA (OR 3.76, 95% CI 1.3 to 11). CONCLUSIONS: This case-controlled study of the influence of SMT and cervical arterial dissection shows that SMT is independently associated with vertebral arterial dissection, even after controlling for neck pain. Patients undergoing SMT should be consented for risk of stroke or vascular injury from the procedure. A significant increase in neck pain following spinal manipulative therapy warrants immediate medical evaluation.

Preventive effects of a traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang, on intimal thickening of carotid artery injured by balloon endothelial denudation in rats.

We report here that the traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang (CLM), significantly inhibited the increase in intimal thickening in rat carotid artery injured by balloon endothelial denudation, which mimics many aspects of restenosis after percutaneous coronary intervention (PCI) in humans. CLM, Saiko-ka-Ryukotsu-Borei-to in Japanese, is commonly prescribed for symptoms accompanying hypertension and atherosclerosis in Japanese Kampo medical care. CLM administered orally 1 week before and 1, 4 and 8 weeks after balloon injury inhibited the increase in intimal area, intimal/medial ratio and stenosis ratio. To our knowledge, this is the first report demonstrating inhibitory effects of a traditional Chinese formulation on intimal thickening of carotid artery after balloon injury. It is worth noting that CLM maintained its inhibitory effect up to 8 weeks after balloon injury. The reduction in intimal thickening by CLM could have resulted from inhibition of intimal smooth muscle cell proliferation, which was assessed by immuno-histochemical analysis using monoclonal antibody against proliferating cell nuclear antigen. Therefore, CLM may be a favourable candidate for prevention of restenosis after PCI. Moreover CLM may have a therapeutic value in the prevention of atherosclerosis, because restenosis after PCI is considered to be an accelerated atherosclerosis.

"Shiatsu sympathectomy": ICA dissection associated with a shiatsu massager.

Carotid dissection is a well-described complication of head and neck trauma. Two cases of carotid dissection that occurred after use of shiatsu-type massagers are described. This potential cause should be considered when evaluating patients with idiopathic carotid dissection.