Vascular endothelial growth factor is associated with histological instability of carotid plaques (original) (raw)
Related papers
European Journal of Vascular and Endovascular Surgery, 2004
Objective(s). We hypothesized that basic fibroblast growth factor (bFGF) may exert a role in carotid plaque instability by regulating the expression of matrix metalloproteinases (MMP). Methods. Plaques obtained from 40 consecutive patients undergoing carotid endarterectomy were preoperatively classified as soft or hard. Serum bFGF was pre-and postoperatively measured. The release of MMP-2 and MMP-9 in the blood serum, and the activity, production and expression in the carotid specimens was analyzed. Specific anti-bFGF inhibition tests were performed in vitro on human umbilical artery smooth muscle cells (HUASMC) to evaluate the role of bFGF in the activity, production and expression of MMP-2 and-9. Results. Twenty-one (53%) patients had a soft carotid plaque and 19 (48%) a hard plaque. Preoperative bFGF serum levels were higher in patients with soft plaques [soft ¼ 34 (28-39) pg/mL and hard ¼ 20 (17-22) pg/mL-p , 0.001] and postoperatively returned to normal values (when compared to 10 healthy volunteers). The serum levels of MMP-2 in patients' with soft plaques were higher than those in patients' with hard plaques [soft ¼ 1222 (1190-1252) ng/mL and hard ¼ 748 (656-793) ng/mL-p , 0.0001]. MMP-9 serum values were 26 (22-29) ng/mL for soft plaques and 18 (15-21) ng/mL for hard plaques (p , 0.0001). We found increased activity, production and expression of MMP-2 and-9 in soft plaques compared to hard plaques (p , 0.001). In vitro inhibition tests on HUASMC showed the direct influence of bFGF on the activity, production and expression of MMP-2 and-9 (p , 0.001). Conclusions. bFGF seems to exert a key role in carotid plaque instability regulating the activity, production and expression of MMP thus altering the physiologic homeostasis of the carotid plaque.
European Journal of Vascular and Endovascular Surgery, 2010
Objective: A challenge facing clinicians is identifying patients with asymptomatic carotid disease at risk of plaque instability. We hypothesise that locally released angiogenic growth factors contribute to plaque instability. Methods: Carotid endarterectomy specimens from eight symptomatic and eight asymptomatic patients were interrogated for microvessel density and angiogenic growth factor expression histologically using immunofluorescence, and biochemically using quantitative real-time polymerase chain reaction (q-RT-PCR). Bio-Plexä suspension array was used to assess circulating biomarkers in venous blood from the same patients and six healthy age-matched controls. Results: Immunofluorescence demonstrated significantly greater neovessel density in symptomatic plaques (P Z 0.010) with elevated expression of hepatocyte growth factor (HGF) (P Z 0.001) and its receptor MET (P Z 0.011) than in asymptomatic plaques. The q-RT-PCR demonstrated up-regulation of Endoglin (CD105), HGF (P Z 0.001) and MET (P Z 0.011) in the plaques of symptomatic versus asymptomatic patients. Bio-Plexä suspension array demonstrated elevated HGF (P Z 0.002) serum levels in symptomatic versus asymptomatic patients and healthy controls, and decreased platelet-derived growth factor (PDGF) (P Z 0.036) serum levels in symptomatic versus asymptomatic patients. (J. Ghosh), m.a.slevin@mmu.ac.uk (M. Slevin), jv.smyth@cmft.nhs.uk (J.V. Smyth), yvonne.alexander@manchester.ac.uk (M.Y. Alexander), fsinglott@hotmail.com (F. Serracino-Inglott).
Scientific reports, 2015
Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy. EMP/PMPs were quantified using flow cytometry. Bioplex assays profiled systemic inflammatory and bone-related proteins. Immunohistological analysis detailed the contribution of differentially-regulated systemic markers to plaque pathology. Alizarin red staining showed calcification. EMPs and PMPs were significantly higher in patients with carotid stenosis (≥70%) compared to controls, with no differences between asymptomatic vs symptomatic patients. Asymptomatic patients with unstable plaques exhibited higher levels of EMPs, CXCL9 and ...
Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease
British Journal of Surgery, 2001
Background: Angiogenesis is a recognized feature of the atherosclerotic process and has been described in the context of unstable coronary atherosclerotic lesions. The aim of this study was to assess the association between angiogenesis in atherosclerotic carotid plaques and microscopic features of plaque instability, in particular intraplaque haemorrhage. Methods: Consecutive patients undergoing carotid endarterectomy were included. Endarterectomy specimens were divided into their constituent atherosclerotic lesions. Histological sections were prepared and stained with haematoxylin and eosin, and immunohistochemically with an endothelial cell marker (CD34). The quantity of intraplaque haemorrhage was measured in transverse histological sections using computerized image analysis. Microvessel counts were performed in CD34-stained sections and were veri®ed through computerized image analysis.
European Journal of Vascular and Endovascular Surgery, 2009
Objectives: Thrombomodulatory factors have been implicated in plaque instability. The aim was to examine the relationship between thrombomodulatory gene expression, timing of clinical events and plaque histology. Design of Study: Plaques were obtained from 40 consecutive patients undergoing carotid endarterectomy and divided into three groups (group 1, early symptomatic, within 1 month; group 2, late symptomatic, 1e6 months and group 3, asymptomatic). Total RNA was isolated to determine the expression of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), plasminogen activator inhibtor-1 (PAI-1), tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), CD68 and vascular endothelial-cadherin (VE-Cadherin). Results: Expression of t-PA, PAI-1, TF, TFPI, TM, CD68 and VE-cadherin were significantly increased in the early symptomatic group (p Z 0.019, 0.028, 0.018, 0.025, 0.038, 0.016 and 0.027 respectively), but the level of gene expression in the late symptomatic group was indistinguishable from the asymptomatic group. The incidence of plaque rupture and intraplaque haemorrhage was significantly increased in the early symptomatic groups (58% versus 18%/ 18% group 2/3, and 55% versus 6%/9% respectively, p < 0.05 for both). Conclusions: Expression of thrombomodulatory genes is increased in unstable plaques, though levels after 1 month are comparable to asymptomatic plaques. This transient rise may influence plaque instability, and rapid resolution mirrors the clinical reduction in risk of further thromboembolic events. Crown
European Journal of Vascular and Endovascular Surgery, 2005
Objective. To determine the concentration of tissue factor (TF), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor A (VEGF-A) in carotid plaques. Materials and methods. Thirty-eight consecutive patients (20 symptomatic, 18 asymptomatic) undergoing carotid endarterectomy were enrolled into the current study. The concentration of TF, TFPI and VEGF-A in carotid plaque homogenates and blood plasma was measured using enzyme immunoassay. Results. The concentration of TF in carotid plaque homogenates was 60 fold higher than in blood plasma. There were no statistically significant differences between the concentration of TF, TFPI and VEGF-A in symptomatic and asymptomatic plaques. Carotid plaques of diabetic patients contained an increased level of TF and VEGF-A (pZ0.002, pZ0.005). The plaque concentration of VEGF-A was elevated among older patients (pZ0.02). Carotid plaques of non-smokers contained an increased level of TFPI (pZ0.03). The concentration of TF, TFPI and VEGF-A in carotid plaques correlated positively with plasma level of these factors (RZ0.86; p!0.0001; RZ0.91; p!0.0001; RZ0.80; pZ0.001, respectively). A highly positive correlation between concentration of VEGF-A and TF, TFPI in carotid plaques was also observed (RZ0.75; p!0.001; RZ 0.62; p!0.001, respectively). Conclusions. TF, TFPI and VEGF-A concentrations do not differ in atheroma removed from symptomatic and asymptomatic patients but are higher in diabetic patients. There is a highly positive correlation between the level of VEGF-A and TF, TFPI in carotid plaques.
Carotid Plaque Echomorphology and Serum Vascular Endothelial Growth Factor Levels
European Neurology, 2004
Neovascularization in atherosclerotic plaques plays an essential role in the progression and rupture of plaques. Vascular endothelial growth factor (VEGF) is an important angiogenic factor. Echomorphologic evaluation of carotid plaques using computer-assisted imaging was found to have a good correlation with the histology of the lesion. The aim of this study was to investigate whether the serum VEGF level could be a determinant of the echomorphology of the carotid plaque. In 28 carotid plaques causing 60–99% stenosis, serum VEGF levels and the mean gray value (MGV) of three-dimensional image of the carotid plaques were measured. A statistically significant inverse correlation was found between serum VEGF concentrations and MGVs (Spearman’s correlation coefficient: –0.415, p = 0.028). Our finding indicates that in patients with ≧60% carotid stenosis the serum VEGF levels are associated with the echogenicity of the atherosclerotic plaque.
The Histologic Characteristics of Primary and Restenotic Carotid Plaque
Journal of Surgical Research, 1998
Proliferative activity was most pronounced in macrophages associated with intraplaque hemorrhage or Background. Although smooth muscle cell proliferaatheroma. The contribution of inflammatory cells to tion is a prominent feature of restenosis in experimenthe biologic behavior of restenotic lesions requires furtal models, the role of cellular proliferation in the initither investigation. ᭧ 1998 Academic Press ation and progression of carotid restenosis is not well Key Words: restenosis; carotid plaque; cellular prolifdocumented. eration. Methods. Between 1985 and 1995, 35 carotid endarterectomies (CEA) in 34 patients were performed for restenosis. Patient risk factors, cerebrovascular symptoms, and operative findings were recorded. Tissue INTRODUCTION specimens from 29 of these cases and 14 original specimens from the same patient were examined by light Restenosis due to neointimal thickening (NT) or recurmicroscopy (H&E, trichrome, elastochrome, and Alrent atherosclerosis (RA) occurring in 1 to 36% of pacian blue) and immunohistochemistry (a actin, CD 68, tients is the major factor limiting long-term patency fol-vWF, and proliferating nuclear cell antigen (PCNA)) lowing carotid endarterectomy . Although several in order to determine the morphologic characteristics etiologic factors, including age, gender, diabetes, hyperand cellular proliferative activity of the plaque.
European Journal of Vascular and Endovascular Surgery, 2004
Objective. To determine the concentration of selected haemostatic factors (HFs): thrombin -antithrombin complexes (TAT), antithrombin (AT), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1) and D-dimers in carotid bifurcation plaques and to compare plaque composition in different subgroups of patients (mainly those with symptomatic and asymptomatic carotid stenosis). Materials and methods. Thirty-eight consecutive patients (20 symptomatic, 18 asymptomatic) undergoing carotid endarterectomy were enrolled in the study. The concentration of selected HFs in carotid plaques was measured using mainly enzyme immunoassay (ELISA). Simultaneously, the concentration of HFs in plasma was also obtained. Results. Symptomatic plaques contained significantly more TAT complexes (p ¼ 0.03). AT was found only in nine out of 38 carotid plaques and was present mainly in symptomatic carotid plaques (n ¼ 8/9)(p , 0.006). No significant differences were found between symptomatic and asymptomatic carotid plaques with respect to t-PA, PAI-1 and D-dimers concentration. There was an increased concentration of TAT (p , 0.001), t-PA (p , 0.02) and D-dimers (p , 0.02) in carotid plaques of diabetic patients. Patients with coexisting intermittent claudication had elevated levels of D-dimers in carotid plaques (p , 0.02). The only positive correlation was demonstrated between the concentration of AT in plasma and carotid plaques (R ¼ 0.76; p ¼ 0.02).