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Biomedical subjects

E R Edelman

Publications and source records attributed to E R Edelman.

At least 55 records · Page 3Linked to original sources
PubMed1998

Arterial heparin deposition: role of diffusion, convection, and extravascular space.

Transvascular transport has been studied with atherogenic, tracer, and inert compounds such as low-density lipoprotein, horseradish peroxidase, and albumin, respectively. Few studies used vasoactive compounds, and virtually all studies examined entry from the lumen and not from the perivascular space. We compared several mechanisms that govern arterial heparin deposition after administration to the perivascular and endovascular aspects of the calf carotid artery in vitro and the rabbit iliac artery in vivo. In the absence of transmural hydrostatic pressure gradients, heparin deposition following endovascular administration was unaffected by deendothelialization and was indistinguishable from perivascular delivery. Deposition in the former was enhanced by the addition of a pressure gradient and to a greater extent in denuded arteries, indicating that convection influences transport but is dampened by the endothelium. Neither the endothelium nor the adventitia pose significant resistances to heparin. Deposition in vivo was greater following endovascular hydrogel release than perivascular application from similar devices to native or denuded arteries. The loss of drug to extra-arterial microvessels exceeded the loss of drug to the lumen flow. These findings are essential for describing vascular pharmacokinetics and for implementing local pharmacotherapies.

Animals↗
PubMed1997

Rat arterial wall retains myointimal hyperplastic potential long after arterial injury.

BACKGROUND: Many novel molecular and pharmacological modalities have been proposed for the treatment of accelerated vascular diseases. Yet the fundamental question remains of whether the vessel wall can be treated once only or whether single-dose therapy simply delays the inevitable processes that lead to intimal hyperplasia. Since platelet adhesion and aggregation are critical events in vascular healing, we sought to determine whether the injured blood vessel would retain its myointimal potential after reversal of even prolonged periods of thrombocytopenia. METHODS AND RESULTS: A novel nonimmune method sustained thrombocytopenia and suppressed postinjury neointimal hyperplasia by 88%. Infusion of fresh platelets, even 14 days after initial denuding injury, restored the full neointimal hyperplastic potential. Platelet depletion presumably removed factors chemotactic for vascular smooth muscle cells but had no effect on the overexpression of the platelet-derived growth factor receptor-beta (PDGFR-beta) subunit after vascular injury. In native vessels, 26.5+/-2.5% of medial smooth muscle cells expressed PDGFR-beta. In all animals, medial PDGFR-beta expression doubled 2 weeks after endothelial denudation and was evident in up to 74.5+/-2.5% of the cells forming the neointima. CONCLUSIONS: Thus, though the hyperplastic potential of the injured blood vessel can be delayed with removal of growth stimuli, it is not lost forever, and if the media is not made quiescent, neointimal hyperplasia is simply delayed rather than prevented. These results may have a profound effect on our understanding and treatment of accelerated proliferative vascular diseases.

Animals↗
PubMed1997

Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels.

The risk of atherosclerosis, a leading cause of cardiovascular disease and death, is inversely related to plasma levels of high-density lipoprotein (HDL) cholesterol, although the mechanism of this protective effect is unclear. The class B scavenger receptor, SR-BI, is the first HDL receptor to be well defined at a molecular level and is a mediator of selective cholesterol uptake in vitro. It is expressed most abundantly in steroidogenic tissues, where it is coordinately regulated with steroidogenesis by adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (hCG) and oestrogen, and in the liver, where its expression in rats is suppressed by oestrogen. Here we show that adenovirus-mediated, hepatic overexpression of SR-BI in mice on both sinusoidal and canalicular surfaces of hepatocytes results in the virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol. SR-BI may directly mediate these effects by increasing hepatic HDL cholesterol uptake or by increasing cholesterol secretion into bile, or both. These results indicate that SR-BI may be important in hepatic HDL metabolism, in determining plasma HDL concentrations, and in controlling cholesterol concentrations in bile, and thus may influence the development and progression of atherosclerosis and gallstone disease.

Adenoviridae↗
PubMed1997

Antisense oligonucleotide inhibition of PDGFR-beta receptor subunit expression directs suppression of intimal thickening.

BACKGROUND: The elucidation of molecular mechanisms of vascular cell biology has markedly influenced our thinking on the pathophysiology of vascular disease. Antisense oligonucleotide gene therapy has helped identify proteins critical to cell-cycle progression and proliferation and possible therapeutic strategies to combat human disease. This approach, however, has not yet been used to examine the contribution of chemotactic proteins and/or their receptors. Platelet-derived growth factor-BB (PDGF-BB) released from activated platelets adherent to subendothelial connective tissue is a principal smooth muscle cell chemotactic factor. METHODS AND RESULTS: A series of experiments was performed to assess the capacity of antisense oligonucleotides to reduce PDGF-beta receptor subunit (PDGFR-beta) expression and the contribution of PDGFR-beta in neointimal formation. Sustained, direct, and local perivascular administration of two different antisense oligonucleotide sequences complementary to PDGFR-beta mRNA almost completely abolished the expression of PDGFR-beta protein in the intima and media of injured carotid arteries and decreased neointimal formation by 80% and 60%, respectively. Furthermore, neointimal formation correlated precisely with PDGFR-beta expression in an exponential fashion. CONCLUSIONS: Thus, myointimal proliferation depends on both PDGFR-beta overexpression and its activation by PDGF-BB. Removal of either of these two elements can suppress neointimal formation.

Animals↗
PubMed1997

Drug clearance and arterial uptake after local perivascular delivery to the rat carotid artery.

OBJECTIVES: We attempted to characterize how drug released into the perivascular space enters the arterial wall and how it is cleared from the local environment. BACKGROUND: Drug released into the perivascular space can enter the artery either from the adventitial aspect or from the lumen after absorption by the extraarterial capillaries and mixing within the systemic circulation. Some investigators suggest that this latter mechanism dominates, and they question whether local drug release is synonymous with local deposition. METHODS: We investigated both the pathways by which adventitially released drug is cleared from the perivascular space and those by which drug enters the blood vessel wall. Inulin was used to follow drug release from implanted devices and subsequent entry to the circulation, because of its first-pass urinary excretion. Heparin was used to follow arterial deposition because of its vasoactivity and tissue-binding properties. The different potential pathways of drug entry and egress were systematically removed and the effects on metabolism and deposition determined. RESULTS: Ligature occlusion of the artery did not decrease inulin excretion or heparin deposition. Extravascular wraps designed to shield the device from extramural capillaries reduced inulin excretion rates 10-fold but did not alter heparin deposition into the vessel wall. The deposition of drug after perivascular delivery was 500 times higher than after intraperitoneal administration. CONCLUSIONS: Although almost all the drug released into the perivascular space is cleared through the extravascular capillaries, virtually all the deposited drug diffuses directly from the perivascular space, and little arrives from the endovascular aspect. These data support the view that local drug release leads directly to increased local drug concentration.

Analysis of Variance↗
PubMed1997

VEGF effect on vascular permeability is mediated by synthesis of platelet-activating factor.

Vascular endothelial growth factor (VEGF), a protein synthesized and secreted by a variety of normal and neoplastic cells, serves as an endothelial cell-specific mitogen and a potent angiogenic factor. Intradermal injection of VEGF increases vascular permeability, a critical event in inflammation and angiogenesis. We sought to identify which tissues are responsive to the inflammatory effect of VEGF, to investigate the mechanisms by which VEGF increases vascular permeability, and to establish whether mediators of inflammation such as platelet-activating factor (PAF) play a role in this regard. Intravenous injection of VEGF (0.001-0.1 nmol/kg) into rats induced dose-dependent protein extravasation in vascular beds of certain tissues up to 177% over control levels. In some tissues, the elevation in vascular permeability in vivo was abolished completely by selective PAF-receptor antagonists. Moreover, VEGF (10(-11) to 10(-9) M) was found to increase PAF synthesis in cultured bovine aortic endothelial cells up to 20-fold. Our results suggest that VEGF increases vascular permeability by inducing PAF synthesis.

Animals↗
PubMed1997

Heparin/heparan sulfate chelation inhibits control of vascular repair by tissue-engineered endothelial cells.

The relative importance of heparin-like compounds in mediating vascular repair is unclear. We investigated how protamine, a chelator of heparin, affected endothelial cell inhibition of vascular smooth muscle cell growth and intimal hyperplasia. The 52% (P < 0.001) reduction in smooth muscle cell proliferation produced by postconfluent endothelial cell-conditioned medium was entirely reversed by pretreatment of medium with heparinase and heparitinase and was inhibited in a dose-dependent fashion by the coadministration of protamine. Pretreatment of conditioned medium with heparinase and heparitinase largely prevented protamine's mitogenic activity, suggesting that protamine affects growth by interacting with heparin-like compounds. Perivascular implantation of polymerengrafted endothelial cells reduced neointima formation in denuded rat carotid arteries by 92% (P < 0.001) and cell proliferation by 81% (P < 0.001). Coadministration of protamine abolished the inhibitory potential of the cell implants, resulting in a nearly twofold exacerbation of intimal hyperplasia compared with controls (P < 0.001). Thus heparin-like molecules are essential to the biochemical regulation of vascular repair provided by endothelial cells, and the continued routine clinical use of heparin chelators, like protamine, may be questionable.

Animals↗
PubMed1997

Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary flow parameters.

Recently, a number of growth factors including basic fibroblast growth factor (bFGF) have been shown to promote angiogenesis in vivo. In this study, we evaluated dose-dependent effect of bFGF administration in the setting of chronic myocardial ischemia. A total of 18 Yorkshire pigs subjected to ameroid occluder placement on the left circumflex artery were randomized to treatment with 10 (n = 6) or 100 microg (n = 5) of bFGF incorporated into heparin-alginate microspheres or inactive control pellets (n = 7). Eight weeks later, all animals underwent angiographic evaluation of collateral development as well as studies of coronary flow and global and regional left ventricular function. Both bFGF groups had significantly higher angiographic collateral index, TIMI flow scores and coronary flow in the ameroid-compromised territory compared with controls. Left ventricular function studies demonstrated improved global and regional function in both fibroblast growth factor groups with significantly better preservation of regional wall motion in high dose (100 microg) bFGF animals. We conclude that local perivascular delivery of bFGF results in significant improvement in myocardial function in the setting of chronic myocardial ischemia.

Animals↗
PubMed1997

DNA antisense strategies in the study of receptors for vasoactive peptides, and of growth and wound-healing factors.

Antisense oligodeoxynucleotide technology has contributed greatly to the overall understanding of both mRNA stability as well as translational processes leading to protein synthesis. Arrest of translational processes by DNA antisense strands usually reduces maximal effects of agonists without affecting their apparent affinities in treated isolated vascular or nonvascular preparations. In the present study, examples are given of DNA antisense oligonucleotide-induced repression of receptors for endothelins, kinins as well as of the platelet-derived growth factor. Furthermore, the efficiency of this technology illustrates the roles of protooncogenes (c-myc and c-myb) in wound-healing mechanisms. The overall mechanism of action of these oligomers is described and the relevance of size, chemical alterations and mode of delivery are illustrated. Release of oligophosphorothioates from polymer matrices and gels can produce a prolonged effect in vivo. Antisense oligonucleotides remain essential in experimental models for which receptor antagonists or selective inhibitors of intracellular components are currently unavailable.

Animals↗
PubMed1996

Regulation by adrenocorticotropic hormone of the in vivo expression of scavenger receptor class B type I (SR-BI), a high density lipoprotein receptor, in steroidogenic cells of the murine adrenal gland.

The class B, type I scavenger receptor, SR-BI, binds high density lipoprotein (HDL) and can mediate selective uptake of HDL cholesteryl esters by cultured cells. The high levels of expression of SR-BI in steroidogenic tissues and the importance of selective uptake from HDL as a source of cholesterol for steroidogenesis raised the possibility that SR-BI may participate in cholesterol delivery to steroidogenic tissues in vivo. We have used immunoblotting and immunohistochemical methods to show that SR-BI is specifically expressed in a distinctive pattern on the surfaces of steroid-producing cells in the murine adrenal gland's cortex and that its expression in vivo is induced by adrenocorticotropic hormone and suppressed by glucocorticoids. Thus, expression of SR-BI protein is coordinately regulated with adrenal steroidogenesis. These data provide strong support for the hypothesis that SR-BI is a physiologically relevant HDL receptor that provides substrate cholesterol for steroid hormone synthesis.

Adrenal Glands↗
PubMed1996

Endogenous cell seeding. Remnant endothelium after stenting enhances vascular repair.

BACKGROUND: Endothelial integrity is essential for maintaining vascular homeostasis, and endothelial denudation results in neointimal thickening. Balloon-expandable endovascular stents provide a luminal scaffolding within atherosclerotic arteries with minimal direct contact between balloon and endothelium. We wondered whether stents cause diminished endothelial ablation, and if so, whether the degree of endothelial damage might determine later proliferative sequelae. METHODS AND RESULTS: Stainless steel stents were expanded in normal or previously denuded iliac arteries of New Zealand White rabbits. Stented arteries were harvested 15 minutes, 1 hour, 3 days, or 14 days later. En face staining of the luminal surfaces of stented arteries demonstrated that endothelial cell loss began immediately after stent expansion and was restricted to interstices between stent struts. Remnant endothelium adjacent to struts provided the foundation for complete endothelial regeneration of the stented segment within 3 days. Both early monocyte adhesion and later intimal macrophage accumulation were reduced > 80% in nonballooned but stented arteries, in concert with a twofold reduction in intimal thickening after 14 days, compared with arteries completely denuded with a balloon before stent expansion. CONCLUSIONS: It is accepted that deep injury caused by balloon-expanded endovascular stents is a critical contributor to experimental stent-induced neointimal hyperplasia. Our data indicate that the degree of endothelial injury may also be an important component of vascular repair after stenting and an important consideration in stent and balloon design and use. The use of stents for primary endovascular intervention may allow partial retention of endothelium within treated arteries, thereby modulating vascular repair with less need for adjunctive pharmacological therapy.

Angioplasty, Balloon↗
PubMed1996

Cellular response to transforming growth factor-beta1 and basic fibroblast growth factor depends on release kinetics and extracellular matrix interactions.

The extracellular matrix plays an important role in growth factor biology, serving as a potential platform for rapid growth factor mobilization or a sink for concentrated sequestration. We now demonstrate that when a growth factor binds reversibly to the matrix, its effects are augmented by this interaction, and when the factor is absorbed irreversibly to the extracellular matrix, it becomes sequestered. These findings call into question the notion that all growth factors are best presented to cells and tissues in a sustained and controlled fashion. In our studies, we examined basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) release kinetics from synthetically fabricated microsphere devices and naturally synthesized extracellular matrix. While the sustained release of bFGF was up to 3.0-fold more potent at increasing vascular endothelial and smooth muscle cell proliferation than bolus administration, the reverse was true for TGF-beta1. A bolus of TGF-beta1 inhibited vascular cells up to 3.8-fold more efficiently than the same amount of TGF-beta1 if control-released. Both growth factors bound to the extracellular matrix, but only bFGF was released in a controlled fashion (2.8%/day). Contact with the extracellular matrix and subsequent release enhanced bFGF activity such that it was 86% more effective at increasing smooth muscle cell numbers than equal amounts of growth factor diluted from frozen stock. TGF-beta1 remained tightly adherent. The small amount of TGF-beta1 released from the extracellular matrix was approximately 30% less effective than bolus administration at inhibiting vascular endothelial and smooth muscle cell growth. Sustained growth factor release may be the preferable mode of administration, but only when a similar mode of metabolism is utilized endogenously.

Animals↗
PubMed1996

Tissue average binding and equilibrium distribution: an example with heparin in arterial tissues.

Classical pharmacokinetic descriptions do not adequately predict the dynamic and complex drug deposition patterns that follow some novel delivery techniques, in part because they do not characterize binding within intact tissues in sufficient detail. In this study, the binding site density of all the potential sites, the tissue-average dissociation constant, and the fractional volume in which heparin can distribute in arterial tissues were measured by incubating tissue samples to equilibrium in solutions containing a wide range of drug concentrations. An "equilibrium distribution curve" was constructed by plotting the concentration of drug in each sample against the concentration in the corresponding bulk phase. The above constants were determined by computationally fitting this curve to a model of drug distribution within tissues. The binding site density was measured to be 4.2 microM, 2.5 microM and 2.2 nM in porcine carotid media with intact and denuded endothelium, and adventitia, respectively. The dissociation constant of heparin in these tissues was estimated to be 6.8 microM, 5.0 microM, and 8.1 nM, respectively. The fractional tissue volume of distribution was 0.61, 0.70, and 0.87, respectively. These values are consistent with known properties of the heparin-arterial tissue interaction. Thus, this technique describes the cumulative effects of binding of a compound to all of its potential binding sites, and will be essential to new detailed descriptions of drug distribution.

Animals↗
PubMed1996

Characterization of glucose-mediated insulin release from implantable polymers.

We characterized a glucose-sensitive, controlled-release insulin delivery system. Insulin release rates increased when glucose was perfused in the release media surrounding the matrix. The system was composed of solid, particulate insulin, incorporated into an ethylene-vinyl acetate copolymer (EVAc) matrix. Feedback control was mediated by the glucose oxidase enzyme immobilized to Sepharose beads, which were incorporated along with insulin into the EVAc matrix. When glucose in solution entered the insulin delivery system, gluconic acid was produced, causing a drop in the microenvironmental pH of the matrix. This fall in pH resulted in a rise in insulin solubility and consequently a rise in the insulin release rate from the matrix. Insulin concentrations increased in vitro and in vivo in response to glucose infusion. The increased insulin release was shown to consist of a finite pulse of insulin that required an optimal recovery period of 1 h to achieve a maximal repeated response to a glucose stimulus. Repeated pulses were demonstrated over a 4 h period. An optimum enzyme ratio was also determined.

Animals↗
PubMed1996

Quantification of insulin release from implantable polymer-based delivery systems and augmentation of therapeutic effect with simultaneous release of somatostatin.

Insulin injections control diabetes mellitus but do not reproduce physiologic regulation. Polymer-based controlled-release technology has enabled us to demonstrate: that the controlled release of insulin from polymer matrices can indeed be used to control diabetes mellitus but does so at the expense of hyperinsulinemia and hypoglycemia; and that somatostatin can be delivered in similar fashion, so as to provide glucose homeostasis in a more physiologic range, at lower insulin levels and at somatostatin doses below those used in intermittent infusion studies; and, that microgram quantities of a drug can be delivered successfully in vivo with intact biological function and in a manner that can be monitored continuously. In the present study the simultaneous polymer-matrix-controlled release of insulin with somatostatin extended glycemic control in diabetic rats. Eleven rats received subcutaneous polymer matrix implants containing insulin alone and 11 rats received implants containing insulin and somatostatin. Plasma and urinary glucose control were improved in both groups. Glucose concentrations in the insulin alone group remained depressed for 5 days until insulin release from the matrices declined below 11.6 units/kg/day. When somatostatin was delivered at 0.75-1.1 micrograms/kg/day together with insulin, plasma glucose control persisted for 12 days until insulin release decreased below 3.6 units/kg/day. It is our hope that further experiments regarding the potential role of both controlled-release devices and somatostatin will be performed to provide continuing therapeutic alternatives to the insulin-dependent diabetic. This is also the first in vivo demonstration of the simultaneous release of two biologically active peptide hormones from polymer matrices. The use of the polymer matrix systems may not only have profound effects on the ambulatory care of diabetes but might also permit the investigation of the synergistic effects of other families of compounds.

Animals↗