Jack C. Geer

Role of the pericyte in wound healing: An ultrastructural study☆

Abstract Mesenchymal cells present in early wounds were divided into two groups: primitive mesenchymal cells and macrophages. Primitive mesenchymal cells appeared to become incorporated in the thick basement membrane of recently formed capillaries, and they also appeared to differentiate into fibroblasts. After becoming encased in vascular basement membrane these cells, pericytes, featured areas of cytoplasmic contact with underlying endothelium. It is proposed that the pericyte-endothelial “contacts” act as a regulatory mechanism for capillary proliferation.

Role of hydroxyl radical scavengers dimethyl sulfoxide, alcohols and methional in the inhibition of prostaglandin biosynthesis.

Prostaglandin biosynthesis from eicosa-8, 11, 14-trienoic acid in microsomes from bovine seminal vesicles is inhibited by relatively high concentrations of hydroxyl radical scavengers: dimethyl sulfoxide, n- and t-butanol, and methional. Methional is a more effective scavenger than t-butanol and dimethyl sulfoxide, two compounds which are more miscible with water than methional. The synthesis of both PGE and PGF is inhibited with incubation systems that promote PGE formation and with incubation systems that promote PGF formation. Furthermore, dimethyl sulfoxide and methional inhibit arachidonic acid-induced platelet aggregation, a reaction involving endoperoxide biosynthesis. The water soluble alcohol, ethanol, stimulates PGF biosynthesis when it is added in the same concentration range as t-butanol. Thus hydroxyl radical scavengers inhibit biosynthesis when their effective concentrations are high and stimulate biosynthesis when their effective concentrations are low. The results of this study and other studies where low concentrations of hydroxyl radical scavengers stimulate both prostaglandin biosynthesis and lipid peroxidation are consistent with a mechanism involving the hydroxyl radical both in the generation of singlet oxygen and the elimination of hydrogen peroxide.

Polyunsaturated fatty acids, vitamine E, and the proliferation of aortic smooth muscle cells

Smooth muscle cell cultures were obtained from the aortas of prepubertal guinea pigs. Cell proliferation in these cultures was inhibited by 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetraenoic acid, and their prostaglandin E derivatives, PGE1 and PGE2. Prostaglandin F derivatives, PGF1α and PGF2α, stimulated cell proliferation. Cell proliferation was also inhibited by 5,8,11-eicosatrienoic acid and 11,14,17-eicosatrienoic acid. The monoene and diene precursors of the triene acids, 9-octadecenoic acid and 9,12-octadecadienoic acid, did not inhibit cell, proliferation. Indomethacin alone had no effect on cell proliferation, and indomethacin did not suppress the inhibition of cell proliferation with a triene acid. The antioxidant α-naphthol alone stimulated cell proliferation and suppressed prostaglandin E formation. α-Naphthol in the presence of either triene or tetraene acids also stimulated cell proliferation and suppressed prostaglandin E formation. The antioxidants butylated hydroxy toluene and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid either alone or in the presence of triene and tetraene acids stimulated cell proliferation and had no effect on prostaglandin E formation. Vitamin E either alone or in the presence of triene or tetraene acids stimulated cell proliferation and had no effect on prostaglandin E formation. More prostaglandin E was formed from 8,11,14-eicosatrienoic acid than from 5,8,11,14-eicosatetraenoic acid in the presence of antioxidants. Vitamin E suppressed the inhibitory effects of both PGE2 and palmitic acid on cell proliferation. The cyclic nucleotide phosphodiesterase inhibitors, caffeine and papaverine, suppressed the stimulatory effect of vitamin E on cell proliferation and enhanced the inhibitory effect of a triene acid on cell proliferation. Substrate and inhibitor specificities are consistent with the oxidative regulation of cell proliferation through the formation of hydroperoxy fatty acids. We propose that hydroperoxy fatty acids may regulate both cyclase and cyclic nucleotide phosphodiesterase enzymes through sulfhydryl-disulfide interconversions. We suggest that this regulatory mechanism may help to explain the acculation of 5,8,11-eicosatrienoic acid in essential fatty acid deficiency, the effects of antioxidants on cell proliferation, and one of the several effects of polyunsaturated fatty acids in proliferative disorders such as cancer and atherosclerosis.

A suggested role for hydrogen peroxide in the biosynthesis of prostaglandins

Abstract Prostaglandin E and F biosynthesis from eicosa-8,11,14-trienoic acid in microsomes from bovine seminal vesicles is inhibited by catalase. Prostaglandin biosynthesis in the same system is also inhibited by 3-amino-1,2,4-triazole (AT) and NaN 3 , reagents which function as heme enzyme inhibitors. AT and NaN 3 inhibit arachidonic acid induced platelet aggregation. Chlorpromazine, a hydroxyl radical scavenger, inhibits platelet aggregation. 1,4-diazabicyclo[2.2.2.] octane, a singlet oxygen scavenger, does not inhibit either microsomal biosynthesis or platelet aggregation. The results are consistent with a mechanism requiring the enzymatic decomposition of H 2 O 2 to a radical, possibly ·OH, in the biosynthesis of prostaglandins.

Positions of double bonds in the monounsaturated alk-1-enyl groups from the plasmalogens of human heart and brain

Abstract The phospholipids of human heart were found to include 16.3 per cent alk-1-enyl acyl glycerophosphorylcholines and 14.9 per cent alk-1-enyl acyl glycerophosphorylethanolamines. A sample of human brain with both gray and white matter contained 0.9 per cent of the former and 22.4 per cent of the latter. Alkyl-1,3-dioxolane derivatives of the alk-1-enyl groups were prepared. The octadecenyl dioxolanes accounted for 18 per cent of the choline plasmalogens and 23 per cent of the ethanolamine plasmalogens from heart and 43 per cent of the ethanolamine plasmalogens from brain. The 18:1 dioxolanes from the heart plasmalogens had a 64:36 distribution of 9,10 and 11,12 double bonds whereas the corresponding value was 30:70 for the brain plasmalogens.

POSITION OF DOUBLE BONDS IN THE FATTY ACIDS OF CHOLESTEROL ESTERS FROM HUMAN AORTA

Abstract Cholesterol ester fatty acids (CEFA) from human aortas with fatty streaks and plaques were analyzed to determine the double bond positions of the unsaturated acids. Aorta CEFA contained a number of polyene fatty acids that were not identified in plasma CEFA. Nearly all the polyene fatty acids found in the aorta were derived from either linoleic or linolenic acid. Since these acids must be derived from the diet, it is presumed that long-chain polyene fatty acids derived from them represent chain elongation and desaturation by cells in the aorta. Polyene fatty acids derived by chain elongation and desaturation of palmitoleic or oleic acids were found in small amounts. The small amount of the 5, 8, 11 isomer of eicosatrierioic acid found suggests that at some point in the evolution of the lesions there is limited availability of linoleic acid.

The gross and histologic appearance and the lipid composition of normal intima and lesions from human coronary arteries and aorta

Abstract Normal intima tissue and individual lesions from coronary arteries and aorta were obtained at autopsy and three plaques were obtained from carotid endarterectomies. Normal appearing intima and lesions were analyzed individually for lipid content and composition. Lesions were classified histologically on the basis of localization of lipid in the intima and in the case of plaque lesions the presence of a fibromuscular cap or zone beneath the endothelium. The lipid composition of each histologic type was determined. Normal intima and individual lesions from coronary arteries and aorta did not differ in absolute or relative triglyceride content. The relative triglyceride content of lesions from both anatomic sites decreased with the development of atherosclerosis. Intracellular lipid lesions and foam cell lesions had the same total and relative lipid composition. The absolute amount and the relative amount of cholesteryl ester increased when these lesions were compared with normal intima (perifibrous lipid). Fibrous plaques were divided into a group containing the same amount of total lipid as normal tissue, a group containing the same amount of total lipid as foam cell fatty streaks, and a group containing much more total lipid than foam cell fatty streaks. The absolute amount and the relative amount of cholesteryl ester were increased when fibrous plaques were compared with normal intima but were not increased when fibrous plaques were compared with intracellular lipid lesions and foam cell lesions (fatty streaks). The relative amount of free cholesterol was increased when fibrous plaques were compared with both normal intima and foam cell lesions but not intracellular lipid lesions. We suggest that the formation of fibrous plaques does not correlate with either a progressive increment in total lipid or a progressive change in relative lipid composition.

Morphology of Mesenchymal Elements of Normal Artery, Fatty Streaks, and Plaques

The objective of this paper is to review briefly normal arterial structure and the cells found in the various types of human atherosclerotic lesions, and to contrast the cellular reaction of human lesions with that in certain experimental models. There is a striking similarity between the mesenchymal cell reaction in human lesions and that in the experimental models, indicating that the models are valid for studying certain aspects of the pathogenesis of atherosclerosis. Our studies support the conclusion of many other investigators (Altschul, 1950; Bjorkerud, 1969; Hassler, 1970; Jores, 1924; Lee et al., 1970; McMillan and Stary, 1968; Poole et al., 1971) that the source of the mesenchymal or smooth muscle cells in the intima is medial cells that have proliferated and migrated into the intima.

Inhibition of platelet aggregation induced by either epinephrine or arachidonic acid

Abstract Inhibitors of arachidonic acid and epinephrine induced human platelet aggregation are described. The metabolic inhibitors 3-amino-1,2,4-triazole, sodium azide and sodium cyanide block arachidonic acid induced aggregation and the second phase of epinephrine induced aggregation but these agents do not block aggregation induced by exogenous ADP. Compounds acting at the alpha-receptor site, phentolamine and 6-hydroxydopamine, inhibit both the first and second phases of epinephrine induced aggregation but not arachidonic acid induced aggregation or aggregation induced by exogenous ADP. Dopamine also inhibits epinephrine induced aggregation without inhibiting either arachidonic acid or ADP induced aggregation. The dopaminergic blocking agent chlorpromazine behaves like 6-hydroxydopamine and dopamine in blocking epinephrine induced aggregation at lower concentrations but chlorpromazine at higher concentrations also blocks arachidonic acid and ADP induced aggregation.

Progression and Regression of Experimental Atherosclerotic Lesions

The prerequisite for development of experimental atherosclerosis in the rabbit and all other experimental models is hyperlipemia. Hyperlipemia can be induced in the rabbit by adding cholesterol to the diet or using a diet with a high content of saturated fat. Lipid infiltration into the wall of the proximal aorta begins within hours following the increase in blood cholesterol1. The earliest lesion morphologically is granular appearing stainable lipid in the interstitial tissue often associated with elastic fibers. Continued hypercholesterolemia eventuates in a foam cellular infiltrate in the intima and inner media associated with proliferation of smooth muscle cells and appearance of a band of smooth muscle cells beneath the endothelial lining1,2. Necrotic cells are found in the lesion usually near the media2. The lipid content of this lesion like that of all other experimental models and man is mostly cholesterol as cholesteryl esters3. The cholesterol in the lesions is derived from the blood4.