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Biomedical subjects

E R Edelman

Publications and source records attributed to E R Edelman.

89 records · Page 5Linked to original sources
PubMed1993

Vascular cell-derived heparan sulfate shows coupled inhibition of basic fibroblast growth factor binding and mitogenesis in vascular smooth muscle cells.

Basic fibroblast growth factor (bFGF) has been previously shown to be mitogenic for vascular smooth muscle cells (VSMCs) in vivo, but only after vascular injury. We show in the present study that the regulation of bFGF-stimulated VSMC proliferation, by vascular cell-secreted heparin-like compounds, correlates with inhibition of bFGF binding to cell-associated heparin sulfate proteoglycans. The stimulation of cultured VSMC proliferation by bFGF was markedly reduced when these cells were cocultured with confluent endothelial cells or confluent VSMCs (100.8 +/- 8.4% and 55.6 +/- 2.3% inhibition, respectively) or with conditioned media from these two cell types. Balb/c3T3 fibroblasts had no statistically significant effect on bFGF-stimulated VSMC proliferation. Vascular cell-conditioned media also inhibited bFGF binding to heparan sulfate proteoglycans on VSMCs, and the inhibition of binding correlated linearly with the inhibition of proliferation after a critical amount of binding was inhibited (44%) (r = .952, P < .0001). Heparinase or heparitinase treatment of conditioned media removed the bFGF-inhibitory effects, presumably by degrading heparin-like compounds. Indeed, heparin itself mimicked the inhibitory effects of conditioned media on bFGF-mediated proliferation and binding to heparin sulfate proteoglycans. These results suggest a bFGF regulatory role for vascular cell-produced heparin-like compounds, linking the mitogenic effects with binding to heparan sulfate proteoglycans for this heparin-binding growth factor.

3T3 Cells↗
PubMed1993

Protamine and protamine-insulins exacerbate the vascular response to injury.

Endothelial cells and smooth muscle cells produce heparinlike compounds that are growth inhibitory for vascular smooth muscle cells, and it has been suggested that these compounds play a regulatory role that is perturbed with vascular injury. Indeed, exogenous heparin preparations effectively suppress smooth muscle cell proliferation following injury imposed on vascular endothelium. We now report that protamine, an agent that binds heparin and negates its anticoagulant properties, has potent stimulatory effects on vascular smooth muscle cell proliferation. The administration of protamine, alone or as part of commonly used insulin preparations, stimulated the proliferation of cultured smooth muscle cells, exacerbated vascular smooth muscle cell proliferative lesions in laboratory rats, and interfered with the growth-inhibitory effects of heparin in culture and in vivo. These results confirm the importance of endogenous heparinlike compounds in arterial homeostasis and may require reconsideration of protamine use following vascular reparative procedures and in diabetics.

Animals↗
PubMed1992

Transforming growth factor beta 1 stimulates the production of basic fibroblast growth factor binding proteoglycans in Balb/c3T3 cells.

Basic fibroblast growth factor (bFGF) binds to cell surface receptors and to heparin sulfate proteoglycans. Heparan sulfate binding may limit bFGF degradation and be an obligatory step for bFGF cell interaction. Transforming growth factor-beta 1 (TGF-beta 1) is a potent regulator of proteoglycan production and composition. The possibility that TGF-beta 1 synergistically regulates bFGF activity by altering bFGF-proteoglycan interactions was investigated. TGF-beta 1 increased 125I-bFGF binding to the extracellular matrix (ECM) of Balb/c3T3 cells 2-4-fold by increasing the number of bFGF binding sites. Increased bFGF binding correlated with a 2-5-fold increase in the production of sulfated proteoglycans, including heparan sulfate proteoglycans. TGF-beta 1 selectively stimulated production of high molecular mass proteoglycans (190-300 kDa) in conditioned medium and stimulated all proteoglycans in ECM. 125I-bFGF bound to TGF-beta 1 induced proteoglycans immobilized onto cationic nylon filters. Furthermore, ECM isolated from TGF-beta 1-treated cells incorporated more mitogenically active bFGF than native ECM. The mitogenic potential of the ECM was significantly reduced by treatment with heparinase. These results suggest that the ability of TGF-beta 1 to stimulate binding of bFGF to ECM, increase ECM heparan sulfate proteoglycan, and potentiate the mitogenic activity of bFGF are linked. Thus one aspect of TGF-beta 1/bFGF synergy may involve modulation of the ECM.

3T3 Cells↗
PubMed1992

Kinetics of basic fibroblast growth factor binding to its receptor and heparan sulfate proteoglycan: a mechanism for cooperactivity.

Basic fibroblast growth factor (bFGF) binds to cell surface receptor (CSR) proteins and to heparan sulfate proteoglycans (HSPG). On the basis of equilibrium dissociation constants (Kd), the CSR has been considered a "high-affinity" binding site and HSPG a "low-affinity" site. We measured the apparent individual on and off rate constants (kon and koff) for bFGF binding to these two sites on intact cells and to each class of binding site in the absence of the other. While the kon's for CSR and HSPG on intact cells were not statistically different (konC = 2.27 x 10(8) M-1 min-1; konH = 0.90 x 10(8) M-1 min-1), the koff for the HSPG was 22.7-fold greater than that for the CSR (koffC = 0.003 min-1; koffH = 0.68 min-1). Thus, the difference in Kd's appears to result from the faster rate at which bFGF is released from the HSPG sites compared to the CSR. The kon's for isolated CSR and HSPG, and the koff for isolated HSPG, did not differ significantly from those for intact cells konC = 2.50 x 10(8) M-1 min-1; konH = 0.92 x 10(8) M-1 min-1; koffH = 0.095 min-1). However, the off rate for isolated CSR (koffC = 0.048 min-1) was statistically indistinguishable from the off rate for HSPG and 16-fold greater than the off rate for CSR on intact cells. The "high-affinity" binding of bFGF to intact cells probably refers only to a complex of bFGF with both CSR and HSPG, and not to the CSR alone.

3T3 Cells↗
PubMed1992

Antisense c-myb oligonucleotides inhibit intimal arterial smooth muscle cell accumulation in vivo.

Synthetic antisense oligonucleotides have been used to dissect gene function in vitro. Technical difficulties prevented the use of this approach for investigating the effect of gene products in vivo. Here we report the use of local delivery of antisense c-myb oligonucleotide to suppress intimal accumulation of rat carotid arterial smooth muscle cells. Our results suggest that antisense oligonucleotides can be used to define the in vivo biological role of specific macromolecules in the blood vessel wall and could potentially serve as a new class of therapeutic agents for cardiovascular disorders.

Animals↗
PubMed1992

Mechanical deformation of polymer matrix controlled release devices modulates drug release.

When magnetic fields were applied to polymer matrices of ethylene-vinyl acetate copolymer embedded with drug and a small magnet, drug release was increased up to 30-fold above baseline levels. It has been hypothesized that the effect of magnetic stimulation on the release of drugs from these matrices is the transduction of the applied magnetic field into a mechanical deformation of the matrix through motion of the magnet within the matrix. This current study provides support for this hypothesis by demonstrating that repeated pulsatile mechanical deformation of matrices can enhance the release of macromolecules from ethylene-vinyl acetate copolymer matrices. Furthermore, similar modulated release kinetics were obtained with mechanically compressed and magnetically stimulated matrices. We also established that modulation was dependent on the ratio of compression area to matrix volume and that modulation was maximized when this ratio was optimized.

Animals↗
PubMed1992

Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries.

Basic fibroblast growth factor (bFGF) is mitogenic for smooth muscle cells (SMC) and angiogenic. We examined the in vivo effects of bFGF in balloon denuded carotid arteries of laboratory rats. bFGF was administered continuously from polymer-based devices at 34 ng/d into the periadventitial space of rat carotid arteries for 2 wk. Intimal hyperplasia was not observed in the absence of injury or with lipopolysaccharide induced endothelial dysfunction. Different degrees of vascular injury produced proportionally more intimal hyperplasia. bFGF increased the intimal hyperplastic response 1.3-fold with severe vascular injury, and 2.4-fold with more mild injury. Increased cell proliferation, not extracellular matrix production, accounted for these effects. Cell density was unchanged for the control and bFGF-treated groups, and the number of proliferating intimal cells at 2 wk rose to an amount equivalent to the increase in mass; 1.9- and 4.0-fold for severe and lesser injury, respectively. The relative ability of heparin to reduce SMC proliferation was not altered by the presence of bFGF.bFGF also induced profound angiogenesis within and surrounding the polymeric releasing device, and in the vasa vasorum immediately around the injured arteries. bFGF's effect on vasa was linearly related to the amount of SMC proliferation within the blood vessel. Thus, the in vivo mitogenic and angiogenic potential of bFGF are coupled, and may be similarly modulated by the products of local injury and/or factors in the vessel wall.

Animals↗
PubMed1991

Controlled and modulated release of basic fibroblast growth factor.

Basic fibroblast growth factor has multivariate effects in stimulating cell growth and the processes that surround tissue repair. Pathophysiologic studies have been hampered by the stability of the compound. Though very potent, basic fibroblast growth factor is rapidly degraded when injected or ingested. Controlled release of basic fibroblast growth factor would allow for examination of the chronic effects of this compound. Conventional matrix polymer-based release devices were fabricated and basic fibroblast growth factor released in a sustained fashion, but 99% of basic fibroblast growth factor mitogenic activity was lost. The source of these losses was identified and preventative measures examined. Preservation and stabilization of basic fibroblast growth factor was accomplished by binding the factor to heparin-Sepharose beads. This permitted prolonged storage, repeated handling, and the encapsulation of basic fibroblast growth factor within a microspherical controlled-release device using a naturally occurring polymer material, alginate. Encapsulation was accomplished with 77% efficiency and 87.5 +/- 12% of the basic fibroblast growth factor was released in a biologically active form. Release activation and regulation was achieved when cleavage of the basic fibroblast growth factor-heparin bonds was enhanced (e.g. by enzymatic bond cleavage with heparinase). Kinetic profiles were identified for a variety of experimental conditions and the effects of the controlled release of basic fibroblast growth factor on BALBc/3T3 fibroblasts examined.

Alginates↗
PubMed1990

Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

Continuous intravenous infusion of heparin suppresses smooth muscle cell proliferation in rats after endothelial injury but may lead to hemorrhage and other complications. The anticoagulant property has been removed from chemically modified heparin without loss of antiproliferative effect but use of such compounds is still limited. In this study ethylene-vinyl acetate copolymer matrices containing standard and modified heparin were placed adjacent to rat carotid arteries at the time of balloon dendothelialization. After 14 days arterial occlusion by smooth muscle cell proliferation was defined. Matrix delivery of both heparin compounds effectively diminished this proliferation in comparison to controls without producing systemic anticoagulation or side effects. In addition, this mode of therapy appeared more effective than the administration of the same agents by either intravenous pumps or heparin/polymer matrices placed in a subcutaneous site distant from the injured carotid artery. Thus, heparin's inhibition of smooth muscle cell proliferation after vascular injury might be most effective within the microenvironment of the injured vessel wall, and the accelerated atherosclerosis or restenosis that often follows angioplasty and other vascular interventions might best be treated with site-specific therapy.

Animals↗
PubMed1987

In vitro and in vivo kinetics of regulated drug release from polymer matrices by oscillating magnetic fields.

The kinetics of drug release from polymer-drug matrices containing an embedded magnet was continuously monitored in vitro and in vivo. The application of an oscillating magnetic field increased the rate of drug release from the polymer matrices. Within the limits of detection the increase in release occurred immediately, remained stable for as long as the field was applied, and returned exactly to baseline upon withdrawal of the field. The increase in release was directly proportional to field amplitude. The same pattern of results were observed in vivo as in vitro, though higher strength fields were required in vivo to achieve the same effect observed in vitro.

Animals↗
PubMed1985

Regulation of drug release from polymer matrices by oscillating magnetic fields.

The reproducible regulation of release of a macromolecule (bovine serum albumin) from biocompatible polymer systems has been demonstrated. Small magnetic spheres or cylindrical magnets were embedded within the polymer matrix which was then subjected to an oscillating magnetic field. In this fashion baseline release rates could be increased 5- to 10-fold with 5-10% standard error. Parameters critical to the regulation of this release included the position, orientation, and magnetic strength of the embedded objects and the amplitude and frequency of the applied magnetic field. Scanning electronmicrographs of the polymer matrix surface reveal that a gap, approximately 100/microns wide, is formed between the embedded object and adjacent polymer material after repeated exposure to an oscillating magnetic field.

Biocompatible Materials↗
PubMed1981

Ocular torsion on earth and in weightlessness.

Ocular torsion (OT) was measured in human subjects during horizontal linear acceleration on a sled in the laboratory and when emerging from weightlessness during parabolic flights in NASA's KC-135 aircraft. Analysis of the frequency response of OT to sinusoidal horizontal oscillation on earth shows results consistent with constant tilt rate studies and with earlier models based on perception of acceleration. Step responses of OT to lateral acceleration are compared to similar profiles from aircraft tests with no preexisting gravitoinertial force on the otoliths. The sensitivity of OT to rotating wide fields producing vection and to tactile cues is compared for earth and weightlessness. A new instrument for high bandwidth video measurement of OT using a soft-contact-lens target is described.

Acceleration↗
PubMedDate not supplied

Diabetic ketoacidosis associated with pheochromocytoma.

A 29-year-old woman was found to have diabetic ketoacidosis associated with classic findings of pheochromocytoma, an association previously undescribed. The patient also had a significant insulin requirement that resolved after tumor excision. Pheochromocytoma with associated hyperglycemia and glycosuria has been reported since 1912, but ketoacidosis has been thought not to occur with pheochromocytoma. The findings in this case are described, and glucose metabolism in pheochromocytoma is reviewed.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

Coated stents: local pharmacology.

Despite excellent restoration of acute vessel perfusion, coronary stenting has been limited by subacute thrombosis within 3-10 days and by neointimal proliferation leading to restenosis by 6 months post-intervention. A variety of pharmacotherapeutics have been utilized in an attempt to prevent these sequelae. Drug regimens that reduce thrombosis have the potential for serious toxicities, and no regimen to date has been shown clinically to reduce the incidence of restenosis. Local drug delivery via stents coated with immobilized drug or coated with a drug-releasing polymer matrix offers the possibility of focal therapeutic drug effect within target tissues without serious side-effects arising from systemic drug administration. Before the promise of this treatment modality is realized, however, a more detailed understanding is needed of the local pharmacologic influences on drug activity. Drug-device parameters, such as stent surface area and mode of drug attachment, and drug-tissue parameters, including drug solubility in and non-specific binding to tissues, interact in a complex manner to determine local tissue drug dose, distribution and, consequently, effect.

Animals↗