Normal rabbits were injected Intravenously with horseradish peroxldase (HRP) and 125 l-labeled human low density lipoprotein (LDL), and the aortas were pertuslon-flxed. Subsequent visualization of HRP In the aortas was produced by reaction of the tissue with diaminobenzldine and hydrogen peroxide. The lumlnal surface of the aortas showed many small punctate foci of brown reaction product to the HRP, which represented penetration of the HRP into the vessel wall. The foci were scattered over the luminal surface, and most of the focal areas were less than 1 mm In diameter. The concentration of LDL was up to 47 times greater in these focal areas than in surrounding noncolored regions not showing Increased permeability to HRP. Small circumscribed foci of heightened permeability to LDL may predispose to the local accumulation of llpld and ultimately to the formation of atherosclerotic plaques. (Arteriosclerosis 6:64-69, January/February 1986) T wo salient features of atherosclerotic lesions are the focal nature of plaque formation and the accumulation of cholesterol, cholesterol esters, triglycerides, and other lipids. The process by which atherosclerotic lesions originate is poorly understood. It is possible, however, that endothelial injury leading to increased arterial wall permeability could be a first stage in atherogenesis. In vivo studies with the protein-binding dye Evans blue 1 " 3 have shown that the dye is taken up preferentially by certain regions of the aortas of rabbits, dogs, and pigs. In pigs these relatively broad regions of enhanced permeability have also been shown to incorporate

SUMMARY By virtue of its location at the interface of flowing blood and vascular tissue, the endothelial cell monolayer is in a unique position for interactions with soluble and cellular elements of the blood on one side and with component cells of the vascular tissue on the other. This brief review outlines humoral and contact-mediated endothelial communication with other cells, particularly the resident cells of the vessel wall. Evidence for gap junctional communication channels between endothelium and vascular cells is summarized and discussed in relation to endothelial ion channel activity. Myoendothelial gap junctional communication is proposed as a mechanism involved in vasorelaxation, either independent of or in concert with secreted endothelium-derived relaxing factor(s). criteria, endothelial cells interact by two general mechanisms with neighboring cells. First, the synthesis and secretion of endothelial products into the extracellular fluid are an effective humoral mechanism for interactions by diffusion and convection to other cells. Second, direct contact between endothelium and other vascular cells occurs in several morphologically defined ways, the most important of which appears to be the communicating gap junction. The types of cells involved in such communication, together with possibilities for their humoral and contact-mediated interactions, are illustrated in Figure 1

Single-dose topical iontophoresis of acyclovir appears to be a convenient and effective treatment for cold sores and merits further clinical investigation.

We developed a method for absolute quantitative autoradiographic measurement of very low concentrations of [125I]-labeled proteins in arterial tissue using Kodak NTB-2 nuclear emulsion. A precise linear relationship between measured silver grain density and isotope concentration was obtained with uniformly labeled standard sources composed of epoxy-embedded gelatin containing glutaraldehyde-fixed [125I]-albumin. For up to 308-day exposures of 1 micron-thick tissue sections, background grain densities ranged from about two to eight grains/1000 micron 2, and the technique was sensitive to as little as about one grain/1000 micron 2 above background, which correspond to a radioactivity concentration of about 2 x 10(4) cpm/ml. A detailed statistical analysis of variability was performed and the sum of all sources of variation quantified. The half distance for spatial resolution was 1.7 micron. Both visual and automated techniques were employed for quantitative grain density analysis. The method was illustrated by measurement of in vivo transmural [125I]-low-density lipoprotein [( 125I]-LDL) concentration profiles in de-endothelialized rabbit thoracic aortic wall.

Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141–150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential more, we designed and synthesized new analogues by linking ɑ-aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals. The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.