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Biomedical subjects

M M Kockx

Publications and source records attributed to M M Kockx.

At least 55 records · Page 3Linked to original sources
PubMed1997

Fibrin(ogen) and von Willebrand factor deposition are associated with intimal thickening after balloon angioplasty of the rabbit carotid artery.

The aim of the study was to assess the contribution of thrombus incorporation into neointimal thickening in the rabbit carotid artery after deep vascular injury induced by balloon angioplasty compared with superficial vascular injury induced by a perivascular collar. Besides CD 31 (PECAM 1), vimentin, alpha-smooth muscle actin, rabbit anti-macrophage monoclonal antibody and proliferating cell nuclear antigen, fibrin(ogen) and von Willebrand factor (vWF) deposition was assessed immunohistochemically. Angioplasty was performed in 47 rabbits and evaluated immediately (n = 7), after 6 hours (n = 4), and after 1 (n = 7), 2 (n = 9), or 3 (n = 20) weeks. A collar was placed in 29 rabbits and evaluated immediately (n = 5), after 6 hours (n = 5), and after 1 (n = 7), 2 (n = 10), or 3 (n = 2) weeks. After dilatation, the arteries were extensively denuded of endothelium, the internal elastic membrane was ruptured and blood-filled clefts were present in the media, pointing to deep vascular (type III) injury. Six hours later, mural fibrin(ogen) thrombi were formed, specially at sites with severe damage. This fibrin(ogen) matrix became infiltrated by phagocytes and smooth muscle cells. A luminal cap covered by regenerating endothelium was formed, demonstrating increased immunoreactivity to vWF. vWF was deposited in the extracellular neointimal spaces. Fibrin(ogen) thrombus deposition and incorporation appeared to be protracted phenomena for at least 2 weeks. After collar placement, minimal endothelial denudation was documented, pointing to focal superficial (type I) vascular injury. In subsequent weeks, neointimal thickening was associated with vWF deposition but not with fibrin(ogen) thrombus incorporation. In conclusion, mural fibrin(ogen) thrombus formation and incorporation contribute to neointima formation after deep vascular injury and seem to occur for several weeks after the initial insult.

Actins↗
PubMed1997

Differentiation, dedifferentiation, and apoptosis of smooth muscle cells during the development of the human ductus arteriosus.

Differentiation of vascular smooth muscle cells (SMCs) is characterized by several molecular transitions. As differentiation proceeds, proteins of the cytoskeletal and contractile apparatus, such as alpha-smooth muscle actin, smooth muscle myosin, calponin, and heavy caldesmon, and the expression of the membrane-related protein smooth muscle phosphoglucomutase-related protein increase, whereas the expression of other proteins, such as fibronectin splice variants with extradomains A (EDA) and B (EDB), decreases. In this study, we investigated the differentiation of the SMCs of the ductus arteriosus during the development of intimal thickening. Ascending and descending aortas of the same age were used for comparison because these vessels lack intimal thickening. In the fetal ductus arteriosus, a relatively early differentiation of the contractile apparatus was observed compared with the ascending and descending aortas. EDA and EDB expression was already low, being similar in the ductus and descending aorta and even lower in the ascending aorta. In the neonatal ductus, SMCs of the media and outer intima were well differentiated and comparable with SMCs of the ascending aorta. Dedifferentiated SMCs, with a low expression of cytoskeletal and contractile proteins and a high expression of EDA and EDB, were found in regions in the inner intima that show features of progression of intimal thickening and in areas of cytolytic necrosis in the media. With a technique using in situ end labeling of DNA fragments, we found extensive apoptosis in the area of cytolytic necrosis and to a lesser extent in these areas of the inner intima. In conclusion, SMCs of the fetal ductus arteriosus have an advanced differentiation of the contractile apparatus compared with the adjacent aorta. Reexpression of fetal characteristics is seen in a number of cells in inner intima and media of the neonatal ductus arteriosus. The finding of apoptosis in these areas suggests that dedifferentiation and apoptosis are associated processes that may play a role in vascular remodeling.

Aorta↗
PubMed1996

Luminal foam cell accumulation is associated with smooth muscle cell death in the intimal thickening of human saphenous vein grafts.

BACKGROUND: Occlusion of saphenous vein grafts is a major problem after coronary artery bypass graft surgery. Diffuse intimal thickening develops in all implanted aortocoronary saphenous vein grafts within 6 months to 1 year. In some regions of the thickened intima, foam cells accumulate along the luminal margin. This particular morphology resembles the morphology of unstable atherosclerotic plaques as they occur in coronary arteries. In the present study, we focused on the possible topographic relation between luminal foam cell accumulation and cell death of smooth muscle cells (SMCs) within the adjacent thickened intima. METHODS AND RESULTS: Segments of occluded and suboccluded implanted human aortocoronary saphenous vein grafts were obtained during reintervention coronary artery bypass graft surgery in 30 patients. In the regions of the vein grafts with luminal foam cell accumulation, the percentage of SMC alpha-actin immunoreactive area of the superficial intimal thickening was 6 +/- 1.4%, which was different from the 17.6 +/- 2.3% of the deep intimal thickening. A strong negative correlation between the number of foam cell nuclei and the percentage of SMC alpha-actin immunoreactive area in the adjacent superficial intimal thickening was present (r = -.77, P < .001). Within the superficial intimal thickening, cytoplasmic and DNA fragmentation could be detected, which points to apoptotic cell death. A fraction of the cytoplasmic fragments fitted the ultrastructural characteristics of matrix vesicles and showed pronounced calcium and phosphorus accumulation as demonstrated with the use of x-ray microanalysis. CONCLUSIONS: The close spatial relation among foam cell accumulation, pronounced intimal SMC loss, and cell death suggests the presence of a foam cell-derived factor that can induce cell death in the SMC population of the intimal thickening. The depletion of the intimal SMC population could promote plaque rupture and thrombotic complications in the grafts.

Cell Death↗
PubMed1996

Balloon angioplasty and induction of non-endothelial nitric oxide synthase in rabbit carotid arteries.

The purpose of the study was to evaluate whether balloon angioplasty is associated with changes in nitric oxide synthase (NO synthase) activity. Normal rabbit carotid arteries were examined 10 min or 1, 2, 3 or 10 weeks after angioplasty with 2 or 2.5-mm balloons. Immunohistology was used to evaluate intimal thickening and endothelial cell regeneration. The NO synthase activity was studied functionally using isolated segments in organ chambers. Immunohistochemistry of the endothelial cell markers von Willebrand factor and platelet endothelial cell adhesion molecule-1 indicated that the regeneration of endothelial cells from patchy islands that remained after angioplasty was virtually complete within 2 weeks. However, the endothelium-dependent relaxations elicited by acetylcholine remained impaired up to 10 weeks after dilation. Contractions elicited by 5-hydroxytryptamine (5-HT) were attenuated, but were significantly augmented by the NO synthase blocker, nitro-L-arginine. Furthermore, in contrast to normal arteries, the balloon-treated arteries developed marked contractions in response to nitro-L-arginine methyl ester (L-NAME), contractions which could be reversed by L-arginine. The latter contractions and relaxations were not influenced by endothelial removal. These results suggest that although the endothelium quickly regenerates after severe balloon injury, the endothelium-dependent release of nitric oxide remains disturbed. However, the functional data also suggest that angioplasty led to a significant induction of NO synthase in 'non-endothelial' cells of the artery.

Angioplasty, Balloon↗
PubMed1996

Centrolobular liver fibrosis in the hypercholesterolemic rabbit.

During a study on the development of atheromatous lesions in rabbits fed a diet with a low or high cholesterol supplement, we found a moderate to pronounced centrolobular liver fibrosis. This fibrosis developed in three stages. Early after supplementation of cholesterol, we observed increased immunoreactivity of collagen types I, III, and IV, and fibronectin, around central veins and in adjacent sinusoids. In the second stage, we observed further increase of collagen and fibronectin immunoreactivity, together with the appearance of alpha-smooth muscle actin (alpha-SM actin)-positive cells and anti-rabbit macrophage monoclonal antibody (RAM 11)-positive cells. In the third stage, we observed large numbers of alpha-SM actin-positive cells, together with heavy deposition of connective tissue proteins in pericentral sinusoids, in addition to focal atrophy of parenchymal cells. By transmission electron microscopy (TEM), fat-storing cells in the pericentral regions were shown to be enlarged, to lose their lipid-droplets, and to acquire dilated rough endoplasmic reticulum corresponding to an activated phenotype. Parenchymal cells were either normal or contained numerous small lipid-droplets. They sometimes were smaller and distorted. Northern hybridization performed on total RNA of whole liver showed an increased level of collagen alpha1(I), alpha1(III), and alpha1(IV) messenger RNA (mRNA) after 24 weeks of low dietary cholesterol supplementation. These data show enhanced expression of extracellular matrix proteins. We conclude that cholesterol overload induces pericentral liver fibrosis in rabbits. The diet clearly activates fat-storing cells to become fibrogenic effector cells. At present, we have no explanation why hypercholesterolemia induces phenotypic transition of fat-storing cells.

Actins↗
PubMed1996

Distribution of cell replication and apoptosis in atherosclerotic plaques of cholesterol-fed rabbits.

In human atherosclerosis the development of a cell-poor lipid-rich core is an important feature of atheromatous plaque formation. The core is characterized by extracellular lipid deposition, cholesterol crystals and cell death and is situated in the deep layer of the plaque. The aim of the present study was to localize apoptotic cell death and cell replication in atherosclerotic plaques of cholesterol-fed rabbits in order to examine the hypothesis that core formation is a consequence of an imbalance between cell replication and apoptosis. New Zealand White male rabbits were fed a diet supplemented with 0.3% cholesterol for 16 (n = 5) and 27 weeks (n = 9). Cell replication and cell types were demonstrated by immunohistochemistry and apoptotic cell death was demonstrated by DNA in situ end-labeling (ISEL) and transmission electron microscopy. Quantification was done using a colour image analysis system. The plaques showed a clear distinction between a luminal layer composed of numerous lipid-rich foam cells of macrophage origin and a deep layer which was fibrous, containing extracellular lipid deposits and few smooth muscle cells. Cell replication (expressed as percentage of total number of nuclei) in the superficial layer was higher then in the deep layer at both 16 (5.1 +/- 1.8% vs. 1.2 +/- 0.8%) and 27 weeks (11.3 +/- 2.1% vs. 4.4 +/- 1.0%). This was also the case for the total number of nuclei per 50000 microns2 cross-sectional intimal area (numerical density): 235 +/- 13 vs. 147 +/- 7 at 16 weeks and 130 +/- 10 vs. 89 +/- 11 at 27 weeks. Apoptotic cell death (expressed as percentage of total number of nuclei) was low and there was no difference between the superficial and the deep layers of the plaques (0.8% +/- 0.2% vs. 0.4% +/- 0.2% at 16 weeks and 0.6 +/- 0.2% vs. 1.7% +/- 0.6% at 27 weeks). Our results indicate that the control of cell number in superficial vs. deep regions of the plaque is mainly a consequence of differences in cell replication. This may be due to a gradient of endothelial and plasma-derived growth factors. Cells can disappear by apoptosis, albeit at a relatively low level, throughout the lesion. This process may contribute to the pronounced cell loss in more advanced human atherosclerotic plaques, setting the base for plaque rupture.

Animals↗
PubMed1996

Primary systemic amyloidosis complicated by massive thrombosis.

We present a case of primary systemic amyloidosis complicated by multiple thrombotic events and initially presenting with a massive thrombosis of the inferior vena cava. Widespread infiltration of the vascular tree by amyloid was found at the time of autopsy. In addition, we report successful treatment of the massive inferior vena cava thrombosis with systemic thrombolysis.

Amyloidosis↗
PubMed1996

Biotin- or digoxigenin-conjugated nucleotides bind to matrix vesicles in atherosclerotic plaques.

The present study analyzes the staining pattern of DNA in situ end-labeling techniques of human and rabbit atherosclerotic plaques. Both the terminal deoxynucleotidyl transferase end-labeling and the in situ nick translation technique detected, besides apoptotic nuclei, numerous round vesicles with diameters from 0.5 to 5 microns within the atherosclerotic plaques. These vesicles did not contain DNA but contained calcium. A pretreatment with EDTA or citric acid abolished the labeling of the vesicles but did not influence the detection of apoptotic nuclei. Ultrastructurally, the vesicles were of variable diameter and density, and their aspect was compatible with matrix vesicles, which are well known in epiphyses during bone formation. The larger vesicles contained cell organelles, and the small vesicles were very dense. X-ray microanalysis demonstrated high calcium and phosphorus levels within the most dense vesicles. Different stages of the process were present in the plaques. In this way we could demonstrate that cytoplasmic fragmentation of smooth muscle cells and subsequent formation of matrix vesicles are a frequent finding in atherosclerotic plaques. The association of apoptotic cell death and formation of matrix vesicles could be an interesting pathway in explaining calcification of atherosclerotic plaques. Both the terminal deoxynucleotidyl transferase end-labeling and the in situ nick translation technique detected simultaneously apoptotic nuclei and matrix vesicles if calcium is not removed from the sections.

Animals↗
PubMed1995

Effect of nitric oxide donors on neointima formation and vascular reactivity in the collared carotid artery of rabbits.

Intimal thickening in arteries is considered a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight twice daily (b.i.d.)] and molsidomine (10 mg/kg body weight/day) can retard neointima formation and changes in vascular reactivity induced by a nonocclusive, soft silicone collar positioned around the left carotid artery of rabbits. The contralateral carotid artery was sham operated and served as a control. Drug and placebo (diet without drug) treatments were initiated 7 days before placement of the collar. At the end of the experiments, two segments were cut from each collared and sham-treated artery, one for measurement of the cross-sectional area of intima and media and the other for isometric tension recording. Sham treatment did not result in intimal thickening in either group. In contrast, the intima/media (I/M) ratio was considerably increased after 14 days of collar treatment as a result of neointima formation. Intimal thickening was significantly inhibited by SPM-5185 (I/M ratio 0.05 +/- 0.01 vs. 0.11 +/- 0.02, p < 0.05), but not by molsidomine (0.06 +/- 0.02 vs. 0.08 +/- 0.02, p = 0.49), which is a donor of both NO and superoxide anions. Neither collar nor NO donor treatment altered the area of the media. SPM-5185 did not alter the percentage of replicating smooth muscle cells (SMC) in the media after collar treatment, as demonstrated by their immunoreactivity for proliferating cell nuclear antigen (PCNA).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Effect of angiotensin-converting enzyme inhibition on intimal thickening in rabbit collared carotid artery.

The positioning of a nonocclusive silicone collar around the rabbit carotid artery results in the formation of a neointima under a morphologically continuous endothelium. We wished to determine whether oral treatment with angiotensin-converting enzyme (ACE) inhibitors prevents or retards intimal thickening and whether this is related to the blood pressure (BP) lowering effects of such drugs. Silicone collars were placed around the left carotid artery of 104 male New Zealand white rabbits for 14 days. The contralateral carotid artery was sham-operated. Three ACE inhibitors were administered from 7 days before collar placement until the end of the experiment: zabicipril (0, 0.03, 0.10, or 0.30 mg/kg/day), moexipril (0, 0.3, 1, or 3 mg/kg twice daily, b.i.d.), and enalapril (0 or 3 mg/kg/day). Each group consisted of 6-12 animals. BP and plasma ACE activity were measured in the nonanesthetized rabbits after 3-week treatment. To evaluate intimal thickening, we measured the cross-sectional area of intima and media. The positioning of the collar led to significant intimal thickening after 14 days. Although the ACE inhibitors decreased BP (zabicipril, 9, 16, 16%; moexipril, 10, 22, 31%; enalapril, 15%) and plasma ACE activity (zabicipril, 87, 88, 92%; moexipril, 79, 92, 93%; enalapril, 88%) significantly and dose dependently, they did not reduce intimal thickening or the cross-sectional area of the media. Angiotensin II does not play a dominant role in collar-induced intimal thickening in rabbits. Furthermore, reducing the BP of normotensive rabbits does not alter neointima formation in this model.

Analysis of Variance↗
PubMed1994

The relationship between pre-existing subendothelial smooth muscle cell accumulations and foam cell lesions in cholesterol-fed rabbits.

We investigated whether pre-existing subendothelial smooth muscle cell (SMC) accumulations in cholesterol-fed rabbits are transformed into foam cell plaques. Twenty-four rabbits received a standard diet supplemented with 2% cholesterol for 4 or 8 weeks. Six rabbits received a supplement of 0.3% cholesterol for 35 weeks. The aorta and other systemic and pulmonary vessels were studied by immunohistochemistry for smooth muscle cells SMC (alpha-SMC actin), macrophages (RAM11), cell replication (proliferating cell nuclear antigen) and endothelial cells (von Willebrand factor; vWF). Initially the foam cell plaques were composed exclusively of foam cells of macrophage origin (MFC). In more advanced lesions SMC and collagen fibres were also present, leading to a fibrous transformation of the plaque. Cell replication was mainly located in the MFC. The endothelial cells covering the plaques showed an increased immunoreactivity for vWF which was also deposited in the interstitium between the FC. Pre-existing subendothelial SMC did not transform into FC. The newly formed FC plaques remained clearly separated from the pre-existing subendothelial SMC. The development of the plaques can be attributed not only to monocyte recruitment but also to macrophage multiplication.

Animals↗
PubMed1994

Duodenal diaphragmlike stricture induced by acetylsalicylic acid.

Many reports have mentioned the role of nonsteroidal antiinflammatory drugs in inducing diaphragm-like strictures in the small and large bowel. These lesions are mostly seen in patients with chronic use of nonsteroidal antiinflammatory drugs. We report the case of a 57-year-old man who developed a diaphragmlike stricture in the second part of the duodenum. The patient had been using a preparation containing acetylsalicylic acid during many years. Although a congenital origin of the diaphragm is not completely excluded, we postulate that this stricture probably occurred as a result of acetylsalicylic acid-induced ulcerations, followed by submucosal fibrosis.

Aspirin↗
PubMed1994

Foam cell replication and smooth muscle cell apoptosis in human saphenous vein grafts.

Occlusion of saphenous vein grafts is a major problem after coronary artery bypass grafting. Segments of occluded and suboccluded implanted aortocoronary grafts were obtained during re-intervention bypass grafting in 47 patients yielding a total of 80 vein grafts. The grafts were studied by immunohistochemistry for smooth muscle cells (alpha-SMC actin), macrophages (HAM56), cell replication (PCNA, Ki-67) and transmission and scanning electronmicroscopy (TEM, SEM). In 81% of the examined grafts the (sub)occlusion was due to a myo-intimal thickening and an associated luminal accumulation of foam cells and mural thrombi. The foam cells were constantly found at the luminal site of the myo-intimal thickening and within the luminal part of adherent thrombi. Transmission electronmicroscopy demonstrated phagocytosis of platelets and platelet fragments by the foam cells. A significant fraction of the foam cells demonstrated nuclear immunoreactivity for Ki-67 and PCNA. The myo-intimal thickening of the vein grafts was composed of smooth muscle cells lying in a fibrous tissue matrix. The smooth muscle cells were surrounded by prominent basal lamina and showed ultrastructural features of apoptosis. Our results support the hypothesis that phagocytosis of lipid rich platelets by monocytes set up a mechanism for foam cell formation and replication in human saphenous vein grafts. The transformation of a smooth muscle cell rich myointimal thickening towards a fibrous, cell poor intimal thickening could be induced by progressive smooth muscle cell loss through apoptosis.

Apoptosis↗
PubMed1993

Longitudinally oriented smooth muscle cells in rabbit arteries.

Intima formation in vessels, spontaneous or experimentally induced, is generally characterized by the presence of longitudinally oriented smooth muscle cells (LSMC). During an experiment of neo-intima induction in carotid arteries in rabbits, by application of a non-constrictive silastic cuff, a study was performed to investigate the presence of LSMC in the systemic and pulmonary circulations, in both elastic and muscular arteries. Three patterns could be distinguished: intimal cushions in muscular arteries, single or small groups of LSMC in the intima in elastic and larger muscular arteries, and intra-medially located layers or columns of LSMC in the aorta, the pulmonary artery, at the bifurcation of the aorta and around orifices of branches. In order to understand this peculiar orientation a biomechanical approach was used: this showed that near the lumen the circumferential stress is 4.5 times higher than the longitudinal. Because the cell surface of the smooth muscle cells exposed to this stress per unit vessel length is much less in the longitudinal than in the circular direction we conclude that the LSMC align in the direction which allows them to cope most effectively with the mechanical stresses.

Animals↗
PubMed1993

Influence of the breathing mode on the time course and amplitude of the cyclic inter-atrial pressure reversal in postoperative coronary bypass surgery patients.

The haemodynamic basis for paradoxical embolization in patients with stroke and decompression sickness has not yet been fully elucidated. Therefore right and left atrial pressures were measured simultaneously with peroperatively placed catheters after coronary artery bypass grafting in 17 patients with sinus rhythm and normal left ventricular function. Recordings were made both during spontaneous breathing and positive pressure ventilation. A cyclic pressure reversal in which right atrial pressure exceeded left atrial pressure was reproducibly recorded. It started on average 215 +/- 5 ms (mean +/- SEM) after the onset of the electrocardiographic P-wave, lasted on average 179 +/- 14 ms and had a maximal amplitude of on average 4.1 +/- 0.3 mmHg. During the expiration phase of spontaneous breathing and inspiration phase of positive pressure ventilation, the onset of the pressure reversal occurred later, its duration was shorter and its amplitude smaller. These observations demonstrate the presence of a cyclic inter-atrial pressure reversal and illustrate the importance of the breathing mode for the time course and amplitude of this reversal.

Adult↗
PubMed1993

The endothelium during cuff-induced neointima formation in the rabbit carotid artery.

Intimal thickening in human arteries is considered as a site of predilection for atherosclerosis. The placement of a flexible, physically nonconstrictive, silicone cuff around the rabbit carotid artery induced a neointima composed of smooth muscle cells (SMCs) within 14 days. To investigate possible alterations of the endothelial cells (ECs) during neointima formation, their morphology was examined with scanning electron microscopy (SEM), transmission electron microscopy (TEM), and confocal microscopy. In the early postoperative period (6 hours), both cuffed and sham-operated arteries demonstrated small foci (5 to 200 microns) of denudation, presumably as a consequence of the manipulation. Within 24 hours the luminal surface of the cuffed and sham-operated arteries was completely covered with endothelium, which remained continuous throughout the study. However, after 1 week the ECs of the cuffed arteries contained a pronounced rough endoplasmic reticulum. From 6 hours until 3 days, polymorphonuclear leukocytes infiltrated the cuffed but not the sham-operated arteries from the lumen. Subendothelial SMC accumulation in the cuffed arteries began after this time period. At day 14 a full-blown neointima composed of longitudinally oriented SMCs had formed in the cuffed arteries. The sham-operated arteries did not develop a neointima. During neointima formation immunoreactivity for von Willebrand factor (vWf) increased in the ECs, and vWf was deposited in the extracellular spaces of the neointima. At day 14 the area of vWf deposits correlated positively with the area of the neointima (r = .73, P < .001). In subsequent weeks, the intimal area did not increase, and vWf deposits vanished from the neointimal matrix. The endothelium of the sham-operated arteries showed no change in vWf immunoreactivity compared with untreated arteries throughout the study. The altered ultrastructural morphology of the ECs and the concurrent vWf deposition in cuffed but not in sham-operated arteries point to alterations in EC function during the development of the neointima. The vWf secretion could possibly lead to increased adhesiveness of the extracellular matrix for the ECs as well as modulate neointima formation.

Actins↗
PubMed1992

The modulation of smooth muscle cell phenotype is an early event in human aorto-coronary saphenous vein grafts.

The morphological changes in human vein grafts occurring in the first days after a coronary bypass operation (CBP) are rarely reported in the literature. Sections of aorto-coronary vein grafts from 11 patients who died during the first 10 days after a CBP were obtained at autopsy. The number of vein grafts per patient ranged from 1 to 4, yielding a total of 28 vein grafts. The early changes in the vein grafts have been studied by light microscopy, immunohistochemistry, transmission and scanning electron microscopy. The study demonstrates that soon after grafting, the vein wall is infiltrated by polymorphonuclear leucocytes (PMN). At 24 h the endothelium shows extensive desquamation. The massive migration of PMN through the venous wall occurs simultaneously with the endothelial damage. The circular layer of the media is severely damaged, resulting in a loss of smooth muscle cells (SMC). The remaining SMC in this layer show a change toward the synthetic phenotype and a reduced expression of alpha-smooth muscle actin. These early changes in the SMC function may initiate the process of fibrosis in the intima and the media of the vein grafts.

Aged↗