Proliferation Of Myointimal Cells Research Articles

Hypertensive nephrosclerosis as a relevant cause of chronic renal failure.

It is currently unclear whether hypertensive nephrosclerosis (HN), usually diagnosed solely on clinical grounds, is a relevant cause of end-stage renal disease. We biopsied 81 hypertensive outpatients (blood pressure >/=160/95 mm Hg) with moderate renal insufficiency, who were referred to our service from 1988 to 1998. Patients with known causes of hypertension, systemic disorders, rheumatic disease, or nephrotic syndrome were excluded. In 65% of patients, HN was the sole histological abnormality associated with renal dysfunction. Benign nephrosclerosis (BN), defined as isolated arteriolar hyalinosis and/or intimal fibrosis, was found in 18 HN patients (22%), whereas malignant nephrosclerosis (MN), denoted mainly by myointimal cell proliferation, appeared in 35 HN patients (43%). Previously undiagnosed primary nephritis (PN) was found in 13 patients (16%), whereas focal and segmental glomerulosclerosis, which might be either primary or secondary to hypertension, appeared in 15 patients (19%). These findings suggest that HN, in both its BN and MN forms, can be a definite cause of chronic renal insufficiency and that a substantial fraction of patients with renal insufficiency and clinical diagnosis of HN may actually have PN.

Dietary l-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits

l-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce the progression of atherosclerosis in cholesterol-fed rabbits. In the present study, we investigated whether myointimal cell proliferation is enhanced in hypercholesterolaemic rabbit aorta and whether chronic treatment of the rabbits with l-arginine or with the NO synthase inhibitor l-NAME influences this proliferative response and vascular monocyte accumulation. Rabbits were fed 1% cholesterol or normal rabbit chow for 12 weeks. Subgroups of cholesterol-fed rabbits were treated with oral l-arginine (2.25%) or l-NAME (3 mg/dl) in drinking water. Myointimal cell proliferation was quantified in aortic segments by immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation into nuclear DNA; vascular monocyte accumulation was assessed by immunohistochemistry using a monoclonal anti-macrophage/monocyte antibody (RAM-11). Plasma levels of l-arginine and the endogenous NO synthase inhibitor, ADMA, were quantified by high-performance liquid chromatography (HPLC). Cholesterol feeding increased the aortic intima/media (I/M) ratio, which was not measurable in the control group, to 1.9±0.3. This was paralleled by enhanced cell proliferation (cholesterol, 2.4±0.2%; P<0.05; control, 0.02±0.001% BrdU-positive cells per 72 h) and vascular monocyte accumulation. Double immunostaining for BrdU and α-actin showed that about two thirds of the proliferating cells were smooth muscle cells. ADMA levels increased from 0.8±0.1 μmol/l to 2.2±0.2 μmol/l in cholesterol-fed rabbits, but were unchanged by l-arginine or l-NAME treatment. Myointimal proliferation and intima/media ratios were correlated with ADMA plasma levels. Dietary l-arginine reduced monocyte accumulation by 85±2% ( P<0.05 vs cholesterol), myointimal cell proliferation (1.8±0.3% per 72 h; P<0.05) and intimal thickening (I/M ratio: 0.7±0.2), whereas the inhibitor of NO synthase, l-NAME, further increased cell proliferation to 3.1±0.4% per 72 h ( P<0.05). No significant difference was observed in vascular monocyte infiltration between the cholesterol and l-NAME groups. We conclude that cell proliferation and vascular monocyte accumulation are enhanced in hypercholesterolaemic rabbit aorta. These atherogenic effects can be attenuated by dietary l-arginine. Decreased NO formation might underlie the enhanced monocyte accumulation and cell proliferation in hypercholesterolaemic rabbit aorta. The observed inhibition of cell proliferation adds to our understanding of the antiatherosclerotic effects of l-arginine in vivo.

Extracardiac vascular and neural lesions in the toxic oil syndrome

The toxic oil syndrome is a multisystemic disease caused by the ingestion of adulterated rapeseed oil. The basic lesion is a peculiar vasculitis that affects mainly the intima, showing the features of an endovasculitis. Vessels of every type and size are involved, affecting practically every organ.The vascular lesion begins with endothelial damage that varies from cellular swelling to cellular necrosis. It then progresses by mixed cellular inflammatory infiltration of the intima and, in some cases, of the media and adventitia. In some cases the infiltrate is rich in eosinophils and a few show foamy histiocytes. Proliferation of myointimal cells and in advanced stages fibroblastic proliferation causes narrowing or obliteration of the vascular lumen. Thromboembolic complications perpetuate the vascular lesion and compound the ischemia and parenchymal atrophy of several organs.The peripheral nerve lesions begin with an inflammatory neuropathy with lymphocytic perineuritis and progress to perineural fibrosis with secondary axonal degeneration. Skeletal muscle lesions exhibit an interstitial inflammatory myopathy at first, followed by a neurogenic muscular atrophy.A direct effect of unidentified toxic substances, possibly free radicals, may cause the endothelial lesion. Other factors, such as immunopathologic mechanisms of delayed hypersensitivity, may contribute to the progression of the vascular lesions.

Accelerated non-muscle contraction after subarachnoid hemorrhage

The cause of chronic cerebral vasospasm after subarachnoid hemorrhage has been studied intensively, but it is still controversial whether the observable luminal narrowing should be attributed to the contraction of vascular smooth muscle cells or whether it results from some organic change in the wall. A proliferation of myointimal cells, accompanied by increased deposition of collagen, as well as myonecrosis, have been frequently observed several days after aneurysm rupture. Studies from our laboratory showed that these myointimal cells had characteristics identical to myofibroblasts. In this study, we quantitatively and morphologically examined the effect of cerebrospinal fluid on the ability of myofibroblasts to alter collagen matrices using an in vitro model. Myofibroblasts contract the collagen matrix by rearranging or compacting the framework of collagen fibers. Cerebrospinal fluid obtained from patients with recently ruptured aneurysms significantly accelerated lattice contraction, especially when the patient developed symptomatic vasospasm. This study suggests that myofibroblasts in the spastic artery can produce a contractile force that contributes to chronic vasospasm, tightening the proliferated collagen. Some unknown agent present in bloody cerebrospinal fluid accelerates the rearrangement of the collagen lattice by myofibroblasts, both of which have, until now, been considered non-contractile components.

Hypercholesterolemia after cardiac transplantation in children

Since the 1980s a steadily increasing number of children have undergone cardiac transplantation. Although graft rejection and complications of immunosuppressive therapy are the leading causes of death in children and adults after cardiac transplantation, coronary atherosclerosis is a significant cause of late mortality. 1,2 Our first pediatric heart transplant patient died suddenly 17 months after transplantation at 3 years of age with severe coronary atherosclerosis. Transplant coronary atherosclerosis may be the result of immune endothelial injury, with a response characterized by proliferation of myointimal cells, thrombus formation, and ultimate intraarterial deposition of lipid material. 3–5 The development of atherosclerosis in transplanted hearts may be enhanced by the presence of hyperlipidemia, both hypertriglyceridemia and hypercholesterolemia. We measured serial lipid levels in 14 children after heart transplantation to assess the prevalence of lipid abnormalities and the usefulness of niacin therapy in children with significant hypercholesterolemia after transplantation.

Accelerated Non-Muscle Contraction after Subarachnoid Hemorrhage: Cerebrospinal Fluid Testing in a Culture Model

Abstract The cause of chronic cerebral vasospasm after subarachnoid hemorrhage has been studied intensively, but it is still controversial whether the observable luminal narrowing should be attributed to the contraction of vascular smooth muscle cells or whether it results from some organic change in the wall. A proliferation of myointimal cells, accompanied by increased deposition of collagen, as well as myonecrosis, have been frequently observed several days after aneurysm rupture. Studies from our laboratory showed that these myointimal cells had characteristics identical to myofibroblasts. In this study, we quantitatively and morphologically examined the effect of cerebrospinal fluid on the ability of myofibroblasts to alter collagen matrices using an in vitro model. Myofibroblasts contract the collagen matrix by rearranging or compacting the framework of collagen fibers. Cerebrospinal fluid obtained from patients with recently ruptured aneurysms significantly accelerated lattice contraction, especially when the patient developed symptomatic vasospasm. This study suggests that myofibroblasts in the spastic artery can produce a contractile force that contributes to chronic vasospasm, tightening the proliferated collagen. Some unknown agent present in bloody cerebrospinal fluid accelerates the rearrangement of the collagen lattice by myofibroblasts, both of which have, until now, been considered non-contractile components.

Morphological studies of cellular responses to experimental arterial grafts

Cross-carotid microvascular bypass grafts 2-3 mm in diameter were implanted using microsurgical techniques for end-to-end anastomosis in four dogs. One autograft control and one of three denatured human umbilical artery xenografts (HUAG) were patent at 5 weeks. One of the other two denatured HUAGs had thrombosed at 1 week, and the other was occluded at 5 weeks. Host and graft vessel specimens were evaluated histologically as well as with transmission electron microscopy after sacrifice. Results indicate that failure of reconstitution of a true endothelial layer, presence of a subintimal myofibroblast population, increased collagen deposition of the muscularis, and occlusion of the adventitial and mural microcirculation were observed in both the early and late nonpatent vessels but not in the patent specimens. Evidence for myointimal cell proliferation was present in both patent and occluded grafts. A cohesive intimal layer was observed in both patent cases. Microvascular occlusion, due to an excess of endothelial cells, of new vasa vasorum in one case seems related to increased fibrosis, which could have resulted in graft stenosis. The surgical procedures and subsequent morphological analyses were adequate and sufficient for use in a long-term study of the possible causes of graft failure.

Intraluminal thrombus and neointimal hyperplasia after microvascular surgery

Despite advances in instrumentation, suture materials, and techniques, thrombosis and intimal hyperplasia due to myointimal cell proliferation are still problems in microvascular anastomosis. Platelet factors stimulate smoothmuscle cell proliferation and migration, but little is known about platelet-vessel wall interaction in microvascular surgery. This study evaluates the effect of the disposition of platelet or luminal thrombus, or both, in intimal evolution in autologous venous micrografts interposed in the common carotid artery of 30 rats. Three hours postoperatively, venous graft and suture line endothelium was completely denuded, and the host artery exhibited focal de-endothelialization. Thrombus deposition was observed on suture line and venous graft luminal surfaces, whereas host artery-denuded areas exhibited platelet adhesion. Two weeks postoperatively, intimal thickenings developed in venous graft and suture line, becoming narrower toward the venous graft. The distribution and size of intimal thickening did not change significantly at later observation periods (3–8 months). Intimal thrombus deposition and intimal hyperplasia, appearing in later stages of evolution, show a similar pattern of distribution.

Effect of hypothalamic stimulation on the endothelial morphology of the aorta in the conscious squirrel monkey

The role of neurogenic factors in the development of atherosclerosis has not previously been studied in detail. In recent years evidence has accumulated to implicate endothelial injury as a primary stimulus for the proliferation of myointimal cells resulting in the formation of the early morphologic lesion. In the present investigation, the effect on aortic endothelial morphology of repetitive electrical stimulation of the lateral hypothalamus in the conscious, unrestrained squirrel monkey, maintained on a cholesterol-free low-fat diet, has been studied. Stimulation was performed with a self-powered, miniaturized electronic stimulator connected to indwelling electrodes. Implanted nonstimulated animals served as controls. Endothelial injury in the form of cell degeneration, denudation, with plasma insudation and partial junctional separation were observed electron-microscopically in stimulated animals compared with controls. These alterations were found to be independent of hypercholesterolemia and/or hypertension. Possible pathways for the induction of injury in this neurogenic model are: (1) direct, through neural circuits from the brain to the vessel wall, and (2) indirect, by elaboration of angiopathic substances inside or outside of the CNS, released into the circulation and transported to the vessel wall where they exert their effects. Reversibility of the endothelial injury or progression to established lesions and mechanisms involved remain to be determined in further investigations.

Atherosclerosis in Macaca mulatta: Histopathological, morphometric, and histochemical studies in aorta and coronary arteries of spontaneous and induced atherosclerosis

A comparative study of morphology, size, and histochemistry of the intimal lesions in aorta and coronary arteries of spontaneously occurring and cholesterol-induced atherosclerosis in rhesus monkeys has been carried out. A group of 30 normal monkeys was also investigated. Spontaneous atherosclerosis was noted in 10 of 55 adult monkeys autopsied serially; fatty streaks or atheroma in the aorta was noted in seven, fibrous plaque was noted in two, and diffuse intimal thickening was observed on one animal only. The coronary arteries showed fibrous intimal thickening without lipid in 8 of these 10 monkeys. There was fair to heavy deposition of acid mucopolysaccharides in the thickened intima along with proliferation of myointimal cells and collagen fibers. In the seven monkeys which were fed an atherogenic diet for 6 months, the aorta showed fatty streaking and atheroma in all animals. The coronary arteries also showed a variable degree of atherosclerosis but the lipid in the thickened intima was not marked. The atherosclerotic plaque height was not significantly greater than that in the spontaneous disease. These differences between spontaneously occurring and cholesterol-induced atherosclerosis in monkeys tend to indicate that the basic mechanism of lesion formation in the two states may be different.

Renal proliferative arteriopathies and associated glomerular changes: A light and electron microscopic study

This presentation reports the light and electron microscopic findings relating to the vascular and glomerular changes in the kidney in a series of 25 patients having malignant hypertension, the hemolytic-uremic syndrome, scleroderma, or toxemia of pregnancy. The pathologic changes were generally similar in each of the diseases studied, the changes being related more to the severity and duration of injury than to the specific disease. Vascular narrowing was due mainly to intimal thickening, and by light microscopy the lesions were categorized as onionskin, mucinous, or fibrous with or without associated elastosis. Intimal erythrocyte extravasation, fibrinoid necrosis, and luminal thrombosis were also seen. Electron microscopy provided additional morphologic information: Myointimal cells were found to be the cellular component in each type of intimal thickening; it was possible to distinguish collagen from large intimal accumulations of basement membrane material; mucinous intimal material was characterized ultrastructurally; and fibrinoid necrosis was identified as a lesion inconstantly associated with cellular necrosis and consisting mainly of fibrinoid material and small deposits of fibrin. It seems likely that there is a common pathogenesis for intimal thickening in a variety of diseases and that this involves endothelial cell damage and increased permeability, leakage of serum and crythrocytes into the intima, and a healing reaction of the vessel wall developing from migration of smooth muscle cells into the intima with subsequent myointimal cell proliferation and fibrogenesis. A common glomerular change in all diseases studied was a striking accumulation of electron lucent material between the endothelium and the lamina densa of the basement membrane. This lesion was interpreted as a manifestation of acute ischemia.

The ultrastructure of acute atherosis in hypertensive pregnancy

Acute atherosis of the myometrial segments of the uteroplacental arteries from pre-eclamptic pregnancies was studied by electron microscopy. The lesions in their early stages are characterized by endothelial damage, insudation of plasma constituents into the vessel wall, proliferation of myointimal cells, and medial necrosis. Fat acculumation is seen first in myointimal cells and, later, macrophages engulf the lipid-rich debris released from disintegrating myogenic foam cells. Gross endothelial damage, massive intramural fibrin deposition, luminal thrombosis, and vessel rupture with hemorrhage are epiphenomena.