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Gerard Pasterkamp

Publications and source records attributed to Gerard Pasterkamp.

53 records · Page 3Linked to original sources
PubMed2003

Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty.

Decorin is a small proteoglycan that binds to transforming growth factor-beta (TGF-beta) and inhibits its activity. However, its interaction with platelet-derived growth factor (PDGF), involved in arterial repair after injury, is not well characterized. The objectives of this study were to assess decorin-PDGF and decorin-PDGF receptor (PDGFR) interactions, the in vitro effects of decorin on PDGF-stimulated smooth muscle cell (SMC) functions and the in vivo effects of decorin overexpression on arterial repair in a rabbit carotid balloon-injury model. Decorin binding to PDGF was demonstrated by solid-phase binding and affinity cross-linking assays. Decorin potently inhibited PDGF-stimulated PDGFR phosphorylation. Pretreatment of rabbit aortic SMC with decorin significantly inhibited PDGF-stimulated cell migration, proliferation, and collagen synthesis. Decorin overexpression by adenoviral-mediated gene transfection in balloon-injured carotid arteries significantly decreased intimal cross-sectional area and collagen content by approximately 50% at 10 weeks compared to beta-galactosidase-transfected or balloon-injured, non-transfected controls. This study shows that decorin binds to PDGF and inhibits its stimulatory activity on SMCs by preventing PDGFR phosphorylation. Decorin overexpression reduces intimal hyperplasia and collagen content after arterial injury. Decorin may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty.

Angioplasty, Balloon↗
PubMed2003

The acute phase protein haptoglobin is locally expressed in arthritic and oncological tissues.

Haptoglobin is an acute phase protein known to be highly expressed in the liver. Recently, we showed increased local arterial haptoglobin expression after flow-induced arterial remodelling and found that haptoglobin is involved in cell migration and arterial restructuring probably through accumulation of a temporary gelatin matrix. Since cell migration and matrix turnover are important features in the pathology of arthritis and cancer, we hypothesized that haptoglobin is also locally expressed in arthritic and oncological tissues. In this study, we investigated local haptoglobin expression in arthritic rats (n = 12) using semi-quantitative PCR and Western blotting, and we studied haptoglobin mRNA localization in human kidney tumours (n = 3) using in situ hybridization. The arthritic rats demonstrated an increase of haptoglobin mRNA (2.5-fold, P < 0.001) and protein (2.6-fold, P < 0.001) in the arthritic Achilles tendon. Haptoglobin protein was also increased in the arthritic ankle (2.6-fold, P < 0.001) but not in the non-arthritic knee. In human kidney tumours, tumour and stromal cells produced haptoglobin mRNA. This study shows that the liver protein haptoglobin is, in addition to the artery, also expressed in arthritic and oncological tissues that are recognized for enhanced cell migration and matrix turnover.

Animals↗
PubMed2002

Nitric oxide synthesis is involved in arterial haptoglobin expression after sustained flow changes.

The acute phase protein haptoglobin is highly expressed in arteries after sustained flow changes and involved in cell migration and arterial restructuring. In the liver, haptoglobin expression is mainly regulated by interleukin-6 (IL-6). In the artery, shear stress and NO influence IL-6 expression. In the present study, we demonstrate that NO synthesis is involved in the regulation of arterial haptoglobin expression after sustained flow changes. Decreased haptoglobin expression after NO inhibition coincided with decreased IL-6 levels. However, IL-6 knockout mice had normal arterial haptoglobin expression levels after sustained flow changes suggesting that other mediators may provide compensatory mechanisms for the regulation of arterial haptoglobin expression.

Animals↗
PubMed2002

In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions.

BACKGROUND: Inflammation plays an important role in atherogenesis. The toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharides and also recognizes cellular fibronectin and heat shock protein 60, endogenous peptides that are produced in response to tissue injury. To explore a possible role for this receptor in arterial obstructive disease, we determined the expression of TLR4 in the atherosclerotic arterial wall, including adventitia, and studied the effect of adventitial TLR4 activation on neointima formation in a mouse model. METHODS AND RESULTS: Localization of TLR4 was studied in human atherosclerotic coronary arteries by immunohistochemistry and detected in plaque and adventitia. In the adventitia, not all TLR4-positive cells colocalized with macrophages. In primary human adventitial fibroblasts, expression of TLR4 was demonstrated by immunofluorescence, Western blot, and reverse transcriptase-polymerase chain reaction. Adding lipopolysaccharide to these fibroblasts induced activation of NF-kappaB and an increase of mRNAs of various cytokines. The effect of adventitial stimulation of TLR4 was studied in a mouse model. A peri-adventitial cuff was placed around the femoral artery. Application of lipopolysaccharide between cuff and artery augmented neointima formation induced by the cuff (intimal area+/-SEM, 9134+/-1714 versus 2353+/-1076 microm(2), P<0.01). In TLR4-defective mice, application of cuff and lipopolysaccharide resulted in a smaller neointima than in wild-type mice (intimal area, 3859+/-904 microm(2), P=0.02 versus wild type). CONCLUSIONS: A functional TLR4 is expressed in human adventitial fibroblasts and macrophages. Adventitial TLR4 activation augmented neointima formation in a mouse model. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation.

Animals↗
PubMed2002

Significance of peptidoglycan, a proinflammatory bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques.

Peptidoglycan (PG) is a major component of the cell wall of gram-positive bacteria that is abundantly present in all human mucosa. PG is a functional lipopolysaccharide analog that binds to CD14 on macrophages and induces proinflammatory cytokine production and metalloproteinases. We investigated the hypothesis that bacterial PG is present in atherosclerotic tissue. In addition, plaque phenotypes were characterized in relation to presence of PG. Immunohistology of carotid (n = 15) and femoral (n = 6) endarterectomy specimens revealed the presence of PG in the cytoplasm of cells located in plaques. PG was detected in 14 of 15 carotid arteries and 5 of 6 femoral arteries. From the 14 coronary arteries, 31 atherosclerotic segments were selected. PG was detected within 19 of 31 of these coronary segments. Western blot demonstrated the presence of the toll-like receptor (TLR-2), the co-receptor for PG, in coronary artery tissue. The number of PG-containing cells in coronary arteries was significantly higher when the histologic features of plaque vulnerability were evident. Inflammation of the cap or shoulder was observed in 11 of 19 PG-positive versus 2 of 12 PG-negative segments (p = 0.023). More than 50% of the plaque area consisted of atheroma in 7 of 19 PG-positive segments and 0 of 12 PG-negative segments (p = 0.025). Heavy smooth muscle cell staining occurred in the plaque cap and shoulder in 3 of 19 PG-positive segments versus 9 of 12 PG-negative segments. Proinflammatory bacterial PG and its co-receptor have been observed in atherosclerotic arteries, in association with the vulnerable plaque phenotype.

Aged↗
PubMed2002

Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring.

Collagen turnover and cell migration are fundamental aspects of arterial restructuring. To identify mRNAs involved in blood flow-induced arterial restructuring, we performed subtraction polymerase chain reaction and found expression of haptoglobin mRNA in adventitial fibroblasts of rabbit arteries. Haptoglobin is highly expressed in liver, but its arterial expression and function are unknown. In vitro studies revealed that stimulation of haptoglobin expression by lipopolysaccharides in mice fibroblasts stimulated migration of wild-type fibroblasts but had no effect on migration of haptoglobin knockout fibroblasts. In vivo studies showed that flow-induced arterial restructuring was delayed in haptoglobin knockout mice. This new function of haptoglobin might be explained by facilitating cell migration through accumulation of a temporary gelatin matrix because cell culture showed that haptoglobin is involved in the breakdown of gelatin. We conclude that haptoglobin is highly expressed in arterial tissue and is involved in arterial restructuring. This new haptoglobin function may also apply to other functional and pathological restructuring processes such as angiogenesis, tissue repair, and tumor cell invasion.

Amino Acid Sequence↗
PubMed2002

Identification of atherosclerotic plaque components with intravascular ultrasound elastography in vivo: a Yucatan pig study.

BACKGROUND: Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated. METHODS AND RESULTS: Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of approximately 4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques (P=0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages (P=0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain >1%) has 92% sensitivity and 92% specificity to identify macrophages. CONCLUSIONS: To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.

Animals↗
PubMed2002

Matrix metalloproteinase inhibition reduces adventitial thickening and collagen accumulation following balloon dilation.

OBJECTIVE: Constrictive arterial remodeling following balloon angioplasty has been related to adventitial collagen accumulation and subsequent thickening and can be prevented by matrix metalloproteinase (MMP) inhibition. Following balloon dilation, we examined the effect of MMP inhibition on collagen turnover and the relationship between adventitial area and degree of constrictive remodeling. METHODS: In 12 non-atherosclerotic landrace pigs, balloon dilation was performed in 39 peripheral arteries with and without MMP inhibition. Follow up with intravascular ultrasound was performed at 42 days. Collagen content was quantified using polarized light and digital image microscopy. Procollagen expression was determined using immunochemistry and Western blotting. RESULTS: In the MMP inhibitor group, constrictive remodeling was inhibited at 42 days follow up. In control and MMP inhibitor groups, a positive relation was observed between adventitial thickness and degree of constrictive remodeling (P<0.001). Adventitial thickening and adventitial collagen content were reduced in the MMP inhibitor group (P=0.002 and P=0.001, respectively). Procollagen immunostaining, but not protein analysis on Western blotting, was decreased in the MMP inhibitor group. CONCLUSION: MMP inhibition impaired adventitial thickening by reduction of collagen content 42 days after balloon dilation. This might explain its inhibitory effect on constrictive remodeling.

Animals↗
PubMed2002

Morphometric and immunohistochemical characterization of the intimal layer throughout the arterial system of elderly humans.

The purpose of the present study was to obtain insight into the natural development of adaptive intimal thickening and atherosclerosis in the arterial tree of human species. The morphometry and composition of the intimal layer were studied in the arterial system of elderly individuals. Post mortem, a total of 703 arterial segments were dissected from 24 subjects (age 81.9 +/- 9.9 years). From each subject, segments were dissected from 31 different arteries. Area stenosis [(plaque area/vessel area) x 100%] was determined in each segment. By (immuno)histochemistry, lipid content and the presence of inflammatory cells (macrophages) were assessed in the coronary, common carotid, brachial, radial and internal iliac arteries. Adaptive intimal thickening or advanced atherosclerosis was observed in all studied artery types. Area stenosis was highest in the coronary arteries (median, 30%) and lowest in the arteries supplying the brain (median, < or = 7%). Plaques hiding a lipid-rich core and plaques with macrophage infiltration were observed in all five selected artery types. In summary, the present observation demonstrates that intimal thickening is a systemic process involving most artery types. Within elderly humans, features of advanced atherosclerotic disease, a lipid-rich core and macrophages, can be observed in the intimal layer of artery types that are recognised for their relation with clinical syndroms as well as artery types that remain clinically silent.

Aged↗
PubMed2002

The contribution of plaque and arterial remodeling to de novo atherosclerotic luminal narrowing in the femoral artery.

BACKGROUND: Atherosclerotic luminal narrowing is caused by plaque growth and arterial remodeling. In peripheral arteries, a role for constrictive remodeling in luminal narrowing has been recognized, but the impact on lumen decrease has not yet been assessed. We studied to what extent arterial remodeling and plaque formation contribute to luminal narrowing in the superficial femoral artery. METHODS: Elderly subjects (n = 79) were studied. Post mortem, pressure-fixed femoral arteries (n = 125) were dissected and divided into 0.5-cm segments (n = 3266). In each cross section, we measured lumen area, plaque area, and the area encompassed by the internal elastic lamina (IEL area). For each artery, the cross section with the least amount of plaque was considered the reference segment. In cross sections with a decrease in lumen area compared with the reference, we determined the contributions of both plaque increase and IEL area change. RESULTS: A decrease in lumen area was found in 2193 cross sections. In cross sections with >50% lumen stenosis, plaque increase (accompanied by IEL area increase) fully explained lumen decrease in 80 of 280 cross sections (29%). In the remaining 200 of 280 cross sections (71%), both plaque increase and IEL area decrease contributed to lumen stenosis. In 57 of 280 cross sections (20%), IEL area decrease was the major determinant of lumen decrease, dominating over plaque increase. In 143 of 280 cross sections (51%), plaque increase was the major determinant, dominating over IEL area decrease. CONCLUSION: The results of this post mortem study suggest that in a substantial part (20%) of severely stenotic lesions in the femoral artery, constrictive remodeling, not plaque size, is the major determinant of lumen decrease. Further serial studies are needed to confirm these results.

Aged↗
PubMed2002

Minimal duration of oral matrix metalloproteinase inhibition to prevent constrictive arterial remodeling after balloon dilation in the pig.

PURPOSE: To determine the minimal duration of oral matrix metalloproteinase (MMP) inhibition to prevent constrictive remodeling after balloon dilation. MATERIALS AND METHODS: In 37 nonatherosclerotic pigs, balloon dilation was performed in 145 peripheral arteries. Pigs were treated with an MMP inhibitor for 2, 7, 14, 28, or 42 days, or they served as controls and were killed 42 days after intervention. Arteries were visualized with angiography and intravascular ultrasonography. RESULTS: A 69% reduction in late vessel area (VA) loss was achieved after 14 days of treatment: 1.27 mm(2) +/- 0.55 (standard error of the mean [SEM]) versus 4.04 mm(2) +/- 0.93 (SEM) in the control group (P =.1). A consistent inhibition of late VA loss was observed in the 28-day (0.89 mm(2) +/- 0.83 [SEM], P =.03) and 42-day (0.74 mm(2) +/- 0.66 [SEM], P =.02) groups treated with the MMP inhibitor. After 14 and 28 days of treatment, late lumen area loss was 65% and 55% of control values, and it decreased to 41% (P =.04) after 42 days of treatment. CONCLUSION: MMP inhibition for 14-28 days is sufficient to inhibit constrictive remodeling after balloon dilation. This implies that an essential MMP-dependent initiator of constrictive remodeling was mainly active in the first 2 weeks after intervention.

Animals↗
PubMed2002

Imaging of atherosclerosis. Remodelling of coronary arteries.

Next to plaque formation, arterial geometric remodelling is an important determinant of luminal narrowing in atherosclerotic disease. Expansive remodelling retards, whereas constrictive remodelling accelerates lumen loss by plaque formation. Expansive arterial remodelling is a double edged sword, however. While luminal area is preserved, the plaque beneath the surface of the lumen often reveals large atheroma with heavy inflammation in expansive remodelling. These characteristics have been associated with plaque rupture and subsequent myocardial infarction. Thus, in the long term expansive remodelling may lead to thrombosis of angiographically silent lesions while constrictive remodelling is often associated with stable coronary syndromes. The mechanisms of arterial remodelling are poorly understood. This is mainly due to lack of good in vitro and animal models which makes mechanistic studies difficult.

Angioplasty, Balloon↗
PubMedDate not supplied

Age-related changes in plaque composition: a study in patients suffering from carotid artery stenosis.

OBJECTIVE: The extent of atherosclerotic plaque burden and the incidence of atherosclerosis-related cardiovascular events accelerate with increasing age. The composition of the plaque is associated with plaque thrombosis and acute coronary occlusion. Surprisingly, however, the relation between advancing age and atherosclerotic plaque composition is still unclear. In the present study, we investigated the association between plaque characteristics and advancing age in a population of patients with haemodynamically significant carotid artery stenosis. METHODS: Patients (N=383), ages 39-89 years, underwent carotid endarterectomy (CEA). Morphometric analysis was performed on the dissected atherosclerotic plaques to study the prevalence of fibrous and atheromatous plaques. Picro sirius red, haematoxylin eosin, alfa actin and CD68 stainings were performed to investigate the extent of collagen, calcification, smooth muscle cells and macrophages in carotid plaques, respectively. The presence of metalloproteinases-2 and -9 was assessed by ELISA. RESULTS: With aging, a decrease in fibrous plaques and an increase in atheromatous plaques were observed. This was accompanied by an age-associated decrease in smooth muscle cell content in carotid plaques. Macrophage content slightly increased with age. In addition, total matrix metalloprotease (MMP)-2 was negatively and MMP-9 positively related with age. Differences in plaque phenotype were most prominent for the youngest age quartile compared with older age quartiles. CONCLUSIONS: With increasing age, the morphology of atherosclerotic plaques from patients with carotid artery stenosis changes. Plaques become more atheromatous and contain less smooth muscle cells with increasing age. Local inflammation and MMP-9 levels slightly increased with age in plaques obtained from patients suffering from haemodynamically significant advanced atherosclerotic lesions.

Actins↗
PubMedDate not supplied

Atherosclerotic expansive remodeled plaques: a wolf in sheep's clothing.

Geometric arterial remodeling is an important determinant of luminal narrowing in atherosclerotic disease. Expansive remodeling retards while constrictive remodeling accelerates luminal narrowing by plaque formation. Cross-sectional as well as follow-up studies revealed that expansive remodeling is associated with adverse cardiovascular events and a vulnerable plaque phenotype. Although the relation between expansive remodeling and plaque vulnerability is associative rather than causal, expansively remodeled plaques should be considered as a wolf in sheep's clothes. Further understanding of the processes that regulate arterial remodeling and plaque rupture may lead to new strategies to responsibly manipulate these processes for the benefit of patient outcomes.

Coronary Artery Disease↗
PubMedDate not supplied

Hemodialysis access graft failure: time to revisit an unmet clinical need?

Hemodialysis (HD) access complications constitute a major cause of morbidity in HD patients. The failure of HD access grafts is predominantly due to progressive intimal hyperplasia (IH) at the venous anastomosis, resulting in a graft flow decline, which ultimately gives rise to graft thrombosis. To date, all tested pharmacological and surgical interventions have not resulted in increased arteriovenous (AV) graft patency rates in HD patients. In this review, we address the mechanisms contributing to AV graft failure and discuss several "emerging" strategies, which could hold promise for optimizing AV graft patency rates. In view of the failure of systemic therapies and the predictable localization of IH, local therapeutic strategies comprise the most promising interventions to improve AV graft patency rates. Based on the large number of promising candidates including drug-eluting stents and brachytherapy, the unmet clinical need for AV graft failure in HD patients is likely to be revisited in the very near future. The biggest challenge, however, remains to translate basic experimental findings into clinical benefits. Simultaneously, continuous efforts should be undertaken to increase the percentage of patients utilizing AV fistulas, which remains the best form of permanent vascular access (VA) for HD.

Animals↗