Endothelial Cell Replication Research Articles

Role of lipoxygenase in the regulation of glucose transport in aortic vascular cells.

Hyperglycemia is closely involved in early and late metabolic, morphologic and pathologic changes leading to the atherosclerosis in diabetes. High glucose levels inhibit replication of vascular endothelial cells (VEC)1–2, but stimulate the proliferation of vascular smooth muscle cells (VSMC)1–5. Hyperglycemia has also been shown to modify extracellular matrix components in blood vessels and to attenuate their production by the vascular cells6–10. Some of these effects result from non-enzymatic glycation of extracellular matrix components and cell-surface proteins by extracellular glucose11–12. Further, intracellular glucose, or its metabolites, affect cell function by modifying cellular metabolism and/or glycation of intracellular proteins13–15 Hyperglycemia also increases oxygen free radical formation in cells and plasma of diabetic patients. These can cause lipid oxidation and damage proteins through cross-linking and fragmentation and be involved in the initiation and progression of the atherosclerotic process16.KeywordsVascular Smooth Muscle CellVascular Endothelial CellHuman Endothelial CellHigh Glucose LevelHyperglycemic ConditionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Lung endothelial cell proliferation in normal and pulmonary hypertensive neonatal calves.

Tremendous changes in pressure and flow occur in the pulmonary and systemic circulations after birth, and these hemodynamic changes should markedly affect endothelial cell replication. However, in vivo endothelial replication rates in the neonatal period have not been reported. To label replicating endothelial cells, we administered the thymidine analog bromodeoxyuridine to calves approximately 1, 4, 7, 10, and 14 days old before they were killed. Because we expected the ratio of replicating to nonreplicating cells to vary with vascular segment, we examined the main pulmonary artery, a large elastic artery, three sizes of intrapulmonary arteries, the aorta, and the carotid artery. In normoxia for arteries < 1,500 micron, approximately 27% of the endothelial cells were labeled on day 1 but only approximately 2% on day 14. In the main pulmonary artery, only approximately 4% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In contrast, in the aorta, approximately 12% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In chronically hypoxic animals, only approximately 14% of the endothelial cells were labeled on day 1 in small lung arteries and approximately 8% were still labeled on day 14. We conclude that the postnatal circulatory adaptation to extrauterine life includes significant changes in endothelial cell proliferation that vary dramatically with time and vascular location and that these changes are altered in chronic hypoxia.

Linomide blocks angiogenesis by breast carcinoma vascular endothelial growth factor transfectants.

The blocking of angiogenesis provides a novel therapeutic target to inhibit tumour spreading. In this study, we investigated the effect of linomide on angiogenesis induced in vivo by highly angiogenic breast carcinoma cells. The rabbit cornea was used to assess neovascular growth in the absence of a tumour mass. MCF-7 cells stably transfected with the cDNA encoding for vascular endothelial growth factor 121 (VEGF121) (V12 clone) were used to elicit a potent VEGF-dependent corneal angiogenesis. After tumour cell implant, albino rabbits received 100 mg kg(-1) day(-1) linomide for 5 consecutive days. Daily observation of neovascular progression indicated that linomide blocked angiogenesis. The antiangiogenic effect of linomide was apparent within 48 h from the beginning of the treatment and was both angiosuppressive and angiostatic. The block of neovascular growth lasted over 10 days from treatment suspension, and preformed vessels, which had regressed, remained dormant, suggesting the persistence of unfavourable conditions for capillary progression. Linomide (50-200 microg ml[-1]) was not cytotoxic in vitro on resting capillary endothelial cells but blocked endothelial cell replication induced by VEGF. Our data indicate that linomide can efficiently and persistently block VEGF-dependent angiogenesis in vivo in the absence of a growing tumour mass. These data suggest that linomide could be a chemopreventive drug in breast cancer patients and a valuable tool in clinical settings in which metastatic spreading occurs in the absence of a detectable tumour mass.

Endothelial Injury in Transgenic (m Ren-2)27 Hypertensive Rats

Transgenic [(m Ren-2)27] rats develop severe hypertension as the result of transfection with the mouse Ren-2 gene. This study tested the hypothesis that hypertensive [(m Ren-2)27] rats have increased endothelial dysfunction by examining the extent of vascular endothelial cell injury and turnover within the thoracic aorta of age-matched female transgene positive [Tg(+)] and transgene negative [Tg(−)] littermates. Transgenic hypertensive rats had arterial pressures significantly higher than Tg(−) animals, but no differences in heart rate or body weight. The extent of endothelial cell injury was estimated in Haütchen preparations of thoracic aorta endothelium by counting cells immunostained for the presence of cytoplasmic immunoglobulin G (IgG) at sites with or without intercostal artery branches. Both Tg(+) and Tg(−) littermates had a greater percentage of injured endothelial cells at branch sites than at nonbranch aorta ( P < .01). However, the number of vascular endothelial cells staining positively for IgG was significantly higher in hypertensive rats both at sites away from ( P < .05) and in the immediate vicinity of ( P < .1) the orifices of intercostal arteries. En face preparations of the thoracic aorta were also examined for cells incorporating 5-bromo-2′-deoxyuridine (BrdU) to estimate the percentage of endothelial cells undergoing replication. There was no difference in endothelial cell replication at either branch or nonbranch sites between hypertensive and normotensive rats. However, the percentage of endothelial cells undergoing replication at branch sites in both Tg(+) and Tg(−) rats was significantly greater than at nonbranch sites ( P < .01). These data provide the first demonstration for the effects of high blood pressure on the vascular endothelium of a monogenetic model of hypertension produced by increased activity of the renin-angiotensin system. The divergent effects of this form of hypertension on vascular endothelial injury and endothelial turnover suggest that the decrease in the reparative capacity of the vascular endothelium induced by the combination of hypertension and associated angiotensinemia may contribute to the endothelial dysfunction accompanying vascular remodeling.

The effect of linomide on the migration and the proliferation of capillary endothelial cells elicited by vascular endothelial growth factor.

In order to assess the mechanism of action of the quinoline-3-carboxyamide linomide as an antiangiogenic drug, the effect of linomide was studied in vitro on postcapillary endothelial cells exposed to vascular endothelial growth factor (VEGF). Linomide did not block the spontaneous replication of endothelial cells, but significantly suppressed endothelial cell growth and migration elicited by VEGF. It is concluded that linomide appears to be an effective tool to inhibit VEGF-dependent angiogenesis.

WR-1065 and Radioprotection of Vascular Endothelial Cells. I. Cell Proliferation, DNA Synthesis and Damage

Normal tissue toxicity limits radiation therapy and could depend on the extent of damage to the vascular endothelium Aminothiols such as WR-1065 [N-(2-mercaptoethyl)-1,3-diaminopropane] provide radioprotection for normal tissues, but little is known about how the aminothiols specifically affect the endothelium. Bovine aortic endothelial cells in culture were exposed to WR-1065 for 2 h before irradiation (137Cs gamma rays, 1 Gy/min). Alone, WR-1065 demonstrated an antiproliferative effect that was related to dose (0.5-4 mM) and was evident by lowered counts of adherent cells 48 h after exposure. WR-1065 was clearly radioprotective when assessed by colony formation and incorporation of [3H]thymidine. However, when the number of adherent cells was evaluated, radioprotection appeared to be slight and evident only in logarithmically growing cells. WR-1065 at 2 mM suppressed single-strand DNA breaks after 3 Gy by 22% and double-strand breaks after 9 Gy by 47%. Also in the irradiated cells, WR-1065 more than doubled the rate of progression of cells from G1 to S phase. WR-1065 pretreatment elevated cellular glutathione (GSH) content more than twofold. Although pretreatment with buthionine sulfoximine inhibited the elevation of GSH, the radioprotective impact of WR-1065 on total DNA strand breaks and colony formation was unaffected. These results suggest that WR-1065 may enable tissue recovery from irradiation by promoting the replication of endothelial cells, possibly by mechanisms independent of GSH.

Vitamin E Restores the Glucose-Induced Impairment of Vascular Endothelial Cell Replication.

We evaluated the effect of vitamin E on the growth of cultured bovine aortic endothelial cells (BAEC). A high concentration of glucose (≥200mg/dl) in the culture medium reduced the replication of BAEC. Addition of vitamin E at a physiological concentration of 6μg/ml restored the impaired replication of BAEC cultured with a high concentration of glucose. Vitamin E had no effect on the growth of BAEC cultured with 100mg/dl glucose. Proliferation of BAEC was not significantly affected by exposure to mannitol at levels equimolar with a high concentration of glucose (600mg/dl), indicating that a high osmolality was not related to the glucose-induced reduction of replication of the cells. BAEC cultured in a high glucose medium may be susceptible to oxidative stress, and the benefit effect of vitamin E may be partly due to a reduction in oxidative damage. Vitamin E may protect endothelial cells against glucose-induced injury.

Hyperlipidemic endothelial injury and angiogenesis.

Hypercholesterolemia is associated with endothelial cell dysfunction which may in part be related to an accumulation of toxic lipoprotein degradation products in artery walls. Oxidized low-density lipoprotein (LDL) and its products have been incriminated in impairing various endothelial functions including G-protein-dependent transmembrane signaling, calcium regulation, phosphoinositide turnover, protein kinase C activation and others. Modification of such cell regulatory functions may alter the responsiveness of endothelial cells to angiogenic (mitogenic) stimuli. Endothelial cell replication is necessary for the growth of preexisting arterial channels and the formation of new microvessels (angiogenesis). Experiments in intact rabbits indicate that endothelial replication necessary for vascular growth is markedly impaired in the presence of hypercholesterolemia, a defect that could play an important role in the pathophysiology of occlusive atherosclerotic disease.

Hypercholesterolemia and angiogenesis

Hypercholesterolemia is associated with endothelial cell dysfunction, which may be partly related to an accumulation of toxic lipoprotein degradation products in artery walls. Oxidized lowdensity lipoprotein and its products have been incriminated in the impairment of transmembrane signaling, a process that may alter the responsiveness of endothelial cells to mitogens. Endothelial cell replication is necessary for the growth of preexisting arterial channels and for the formation of new microvessels (angiogenesis). Experiments in intact rabbits indicate that endothelial replication necessary for vascular growth is markedly impaired in the presence of hypercholesterolemia, a defect that may play an important rote in the pathophysiology of occlusive atherosclerotic disease.

Endothelial cell replication in an in vivo model of aortic allografts

Previous studies of aortic valve allograft viability have used in vitro assessments that may not reflect in vivo properties. This study evaluated in vivo endothelial cell replication in experimental valved aortic grafts and examined the consequences of histoincompatibility and cryopreservation. Valved aortic conduits were heterotopically transplanted into syngeneic or allogeneic rats. Tritiated thymidine was administered to graft recipients and control rats. After 72 hours, monolayers from the native aortas and the aortic portion of the grafts were prepared for autoradiography, with six or more silver grains per nucleus considered evidence of replication. Percentages of replicating cells in native aortas ranged from 0.3% to 2.3% ( p = not significant). Percentages of replicating cells in the fresh isografts (12.4%) and allografts (12.2%) were not significantly different from each other, although each was significantly greater than the percentage in its native aorta ( p < 0.04). Cryopreserved allografts and isografts displayed few endothelial cells, none of which was replicating. Immunologic differences do not affect endothelial cell replication in this early period after fresh graft transplantation. Cryopreservation, however, results in the absence of replicating endothelium.

Oxygen affects human endothelial cell proliferation by inactivation of fibroblast growth factors.

The fibroblast growth factors (FGF), including endothelial cell growth factor (ECGF)/acidic FGF and basic FGF, are important modulators of endothelial cell replication in vitro and in vivo. Premature infants and adults with lung injuries are often treated with high levels of inspired O2, which can be necessary for survival but potentially injurious to developing lungs and in tissue repair following injury. Human umbilical artery and vein endothelial cells were grown in ECGF- or FGF-supplemented Medium 199 and exposed to ambient levels of O2 from 10 to 95%. Endothelial cell growth, measured by [3H]thymidine incorporation, was inhibited by increasing levels of O2 and ceased above 50% O2. Vein endothelial cells could recover from up to 24 h of hyperoxic exposure when given fresh medium, but not after 48 h. Artery-derived cells were more sensitive to O2 than were vein-derived cells. Complete medium without endothelial cells, preincubated 24 h in 95% O2, lost its ability to support cell growth under normoxic conditions. Exposing individual medium components to high O2 demonstrated that purified natural ECGF and recombinant acidic or basic FGF were all inactivated by O2. Human recombinant superoxide dismutase prevented FGF inactivation. O2 inactivation of essential growth factors could thus have major consequences for lung development or repair of injured capillaries in infants or adults inspiring high levels of O2.

Purification of platelet-derived endothelial cell growth inhibitor and its characterization as transforming growth factor-beta type 1.

In 1986, Brown and Clemmons (Proc. natl Acad. Sci. USA 83 (1986) 3321) showed that platelets contain a substance, platelet-derived growth inhibitor (PDGI), that inhibits in vitro endothelial cell replication. Although platelets are rich in transforming growth factor beta (TGF-beta), PDGI was considered not to be related to TGF-beta, on the basis of its reported properties (extraction from platelets at neutral pH, binding to heparin-Sepharose). However, we purified PDGI to near homogeneity and showed that on the basis of HPLC retention behavior, in vitro growth inhibitory activities with several cell types, receptor binding, and immunoneutralization of growth inhibitory activity with specific anti-TGF-beta type 1 antibodies, PDGI is most probably identical with TGF-beta type 1.

Recent insights into coronary collateral circulation.

The functional significance of coronary collaterals in humans has been debated for many years. Correlations have now been made between the anatomic appearance of coronary collateral vessels visualized at the time of intracoronary thrombolytic therapy during the acute phase of myocardial infarction and the creatine kinase time--activity curve, infarct size, and aneurysm formation. These studies demonstrate a protective role of collaterals in hearts with coronary obstructive disease, showing smaller infarcts, less aneurysm formation, and improved ventricular function compared with patients in whom collaterals were not visualized. There is ample evidence that collaterals respond to myocardial ischemia by opening preexistent channels. When the cardiac myocyte is rendered ischemic, collaterals develop actively by growth with DNA replication and mitosis of endothelial and smooth muscle cells. Heparin-binding growth factors are present in the heart, but their biological activity is quiescent under normal physiological conditions. Once ischemia develops, these factors are activated and become available for receptor occupation, which may initiate angiogenesis after exposure to exogenous heparin. This characteristic of heparin to potentiate the mitogenic activity of acidic fibroblast growth factor has recently been used in the clinical setting as a possible therapeutic modality in patients with coronary artery disease. Patients performing 20 rounds of exercise serially after receiving intravenous injection of heparin showed significantly greater increases in exercise capacity and improvement of clinical symptoms compared with the control group who performed the same exercise without heparin. Further study of neovascularization may lead to a new therapeutic strategy for ischemic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Replication of endothelial cells and smooth muscle cells induced in vivo by hypercholesterolaemia and materials released from platelet-rich white thrombus.

Endothelial cell injury is considered to be the primary event in atherogenesis. In this study, we investigated the effects of hypercholesterolaemia, and substances released from platelet-rich thrombi, individually and together on endothelial cells and the wall of the rabbit in vivo. We divided 24 rabbits into four groups: I was a control group on a normal diet; II was a tubing group on a normal diet, in which polyethylene tubing was inserted into the ascending aorta; III was a group being fed a cholesterol diet; and IV was a combined group being fed a cholesterol diet with polyethylene tubing in the ascending aorta. Segments from the descending thoracic and abdominal aortas which were not injured directly by tubing were examined morphologically and for [3H] thymidine incorporation into endothelial cells and smooth muscle cells. The descending aortas of groups II, III, and IV showed various degrees of endothelial cell damage. [3H]Thymidine incorporation into endothelial cells and aortic wall was increased in groups II, III, and IV (most in group IV) as compared with group I. These data indicate that hypercholesterolaemia and substances released from activated platelets and/or white mural thrombi can cause endothelial damage which may result in endothelial and smooth muscle cell proliferation. In addition, a combination of these two factors showed an additive effect on the endothelial injury and regeneration in vivo.

A study of the effects of angiotensins 1, 2, 3 and bradykinin on the replication of bovine retinal capillary endothelial cells and pericytes.

The renin-angiotensin system of the human eye may play a role in the regulation of retinal blood flow and the development of new vessels. We have investigated whether angiotensins 1, 2 and 3 or bradykinin, in concentrations ranging between 1 x 10(-12) and 1 x 10(-6), have any mitogenic activity on cultured bovine retinal endothelial cells (BREC) and pericytes (BRP). Cell replication was assessed by 3H-thymidine incorporation and, in the case of BREC and AT-2, also by cell counts. AT-2 was also tested on bovine aortic EC (BAEC). None of the substances elicited any response on BREC, BRP or BAEC. Whether angiotensin(s) induce angiogenesis in retinal vessels in vivo remains to be established but this does not appear to occur through direct stimulation of cell replication.

Endothelial dysfunction in response to psychosocial stress in monkeys.

The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a beta-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p less than 0.01) but not among their metoprolol-treated counterparts, whose heart rate declined (p less than 0.05). After the social manipulation, all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death), endothelial cell replication, the presence of adherent leukocytes, and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta, immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p less than 0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys, but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with a beta-adrenergic blocking agent.

In situ pulmonary vascular perfusion for improved recovery of pulmonary intravascular macrophages

The microcirculation contains mononuclear phagocytes, with features characteristic of macrophages, adhered to luminal capillary surfaces by intercellular adhesion plaques. These pulmonary intravascular macrophages may play an important role in regulating lung vascular tone and capillary permeability, and may modulate capillary endothelial cell growth and replication by the secretion of soluble mediators (i.e., arachidonate metabolites, cytokines). This study describes a technique which utilizes in situ lung perfusion to remove intravascular macrophages in large numbers from the microcirculation of porcine lung ( n = 26). This technique yielded 3.8 ± 0.5 × 10 8 (mean ± SEM) mononuclear cells which were highly phagocytic toward particulate carbon (phagocytic index, 80 ± 6%). Harvested mononuclear phagocytes reestablished intercellular adhesion plaques when placed on small vessel porcine pulmonary artery endothelial cell monolayers and exhibited histochemical characteristics typical of monocyte/macrophage lineage cells. Mononuclear cells obtained from lung microcirculation displayed size heterogeneity varying from 10.4 to 16.5 μm in diameter. Both large and small cell populations phagocytosed particulate carbon. Morphometric studies performed on collagenase-treated lung demonstrated that in situ perfusion removed significant numbers of intravascular macrophages in lung capillaries. The technique described permits the rapid removal of anchored mononuclear phagocytes from lung capillaries with minimal postmortem delay.

Pathogenesis of corneal oedema associated with herpetic eye disease.

Corneal oedema and stromal disease, induced in rabbits by intrastromal injection of herpes simplex virus, type 1, strain RE (HSV-1, RE), reached a peak of 12-15 days after infection. Corneal oedema as measured by ultrasonic pachymetry, and stromal disease as measured by a subjective scoring system, were closely related for 30 days after infection. Morphometric analysis of wide field specular micrographs showed that no immediate endothelial cell damage occurred in either control or HSV-1 infected corneas. Alizarin red S staining of corneas taken during the period of most severe oedema indicated no significant endothelial cell loss; however, visual inspection indicated numerous staining abnormalities. Scanning and transmission electron microscopy provided evidence of an intact endothelial layer possessing integrated infiltrating cells. Virus antigen could not be detected on endothelial cells by immunoperoxidase staining at any time during development of corneal oedema. The results indicate that corneal oedema associated with HSV-1 induced disease can occur in the absence of detectable virus replication and cytolysis of corneal endothelial cells.

Developmental mechanisms underlying pathology of arteries

This review tries to provide a general, and very speculative, view of growth control mechanisms that may be common to the development of blood vessels and to pathological processes including cell proliferation. From a developmental point of view, vascular growth is most likely to include local autocrine or paracrine mechanisms that permit the two cells of the vessel wall to grow, organize into the characteristic tubular and layered structures of the vessel wall, and eventually achieve a return to quiescence. The "real" mechanisms controlling growth in vivo are difficult to ascertain from studies in culture. For example, a large list of angiogenesis molecules must be able to generate endothelial replication, but in culture many of these molecules are inhibitory for each endothelial replication. Similarly, in culture, we have a long list of smooth muscle mitogens, but none of these have as of yet been proven to control smooth muscle growth in vivo. Endothelial growth control has been attributed to the presence of membrane molecules able to inhibit endothelial replication and to the actions of soluble growth factors and their receptors. Unfortunately for the former hypothesis we still lack specific molecules with the properties of contact inhibition of replication. The data discussed here, however, suggest that modulation of expression or function of cell-cell adhesive molecules could be critical both to morphogenic changes and to mitogenesis by release of cells from cell-cell contact. Moreover, our data and data from other laboratories suggest that angiogenic factors, including the HBGFs and TGF-beta, may function in angiogenesis by altering cell-cell and cell-cell substrate interactions rather than via a primary effect on cell replication. This view of angiogenesis is consistent with the absence of a mitogenic effect of some angiogenic factors. Although endothelial cell replication is obviously necessary to angiogenesis, the lack of mitogenic effect of some factors suggests a need for a more general explanation of the actions of angiogenic factors. Endothelial injury may be interrelated with smooth muscle growth. The simplest possibility is that a failure of the endothelial cell barrier function, due either to denudation or an increase in adhesivity for leukocytes, would permit access of platelets or leukocytes to the vessel wall. These extrinsic cells, in turn, would stimulate smooth muscle cell replication by release of growth factors. The second possibility is that the endothelial cell may itself release growth factors into the vessel wall.(ABSTRACT TRUNCATED AT 400 WORDS)

Uremic levels of oxalic acid suppress replication and migration of human endothelial cells.

Patients with chronic renal failure who undergo hemodialysis experience accelerated atherosclerosis and premature death. Since the end-metabolite, oxalic acid, accumulates in plasma in proportion to the severity of renal failure, we studied whether sodium oxalate (0 to 300 microM) is an endothelial toxin and, therefore, might enhance atherogenesis. Exposure to uremic levels of oxalate (greater than 30 microM) for 9 to 28 days depressed endothelial cell replication by 33% to 84% (mean +/- SD, 54% +/- 15.7%, n = 17 experiments, p = 0.002). In contrast, replication of fibroblasts exposed to 200 microM oxalate for 45 days was not inhibited. The inhibitory effect of oxalate on endothelial cell replication was both dose- and time-dependent (both p less than 0.0001) and was first detected 3 to 7 days after the initial exposure to oxalate. Further, the inhibitory effect was fully reversible upon removal of oxalate, but only if exposure was limited to 5 days or less. Sodium salts of other carboxylic acids (citric, succinic, glyoxylic, and malonic; 200 microM) as well as HCl (200 microM) did not suppress endothelial cell replication. Oxalate also inhibited endothelial cell migration but had no effect on basal, thrombin-induced, or arachidonate-induced prostacyclin production by endothelial cells. Exposure of endothelial cells to sodium oxalate (200 microM) for as little as 24 hours-a time period sufficient to induce delayed, transient inhibition of replication not detectable until approximately 1 week after exposure-inhibited incorporation of 3H-leucine into protein by 40% (p = 0.009). We conclude that sodium oxalate acts as a uremic toxin, inhibiting endothelial cell replication and migration, functions which may be important for constitutive inhibition of atherosclerosis.