摘要:

Endothelial injury or dysfunction has been proposed to be one of the initiating events of atherosclerosis and is associated with an apparent decrease in the production of the vasodilator autacoid nitric oxide (NO). The nature of the endothelial dysfunction resulting in an attenuation of NO-mediated responses is unknown although possibilities include decreased substrate availability, decreased expression of the NO synthase, imbalance between the production of endothelium-derived constricting and relaxing factors, production of an endogenous NO synthase inhibitor and overproduction of oxygen-derived free radicals. While experimental evidence has been provided to support almost all of these possibilities, increased production of superoxide anions within the vascular wall is currently favoured as an explanation for the observed changes in vascular responsiveness and the characteristic loss of the anti-adhesive properties of the endothelium in the early stages of atherosclerosis. The altered ratio of NO/superoxide anion (O2 production has been proposed to alleviate intrinsic inhibition of the transcription factor NFkB and lead to enhanced expression of adhesion molecules and chemotactic factors at the endothelial surface. The aim of this short review is to summarise recent findings which suggest that an imbalance in the production of NO and O2 within the vascular wall is one of the earliest events to occur in the atherogenic process.

ISSN:1018-1172    

DOI:10.1159/000159147

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The present study focuses on the differential response of three branch levels of the mesenteric resistance arterial vasculature of 450-gram Sprague-Dawley rats infused continuously with angiotensin II (A-II) for 4, 7 and 14 days at a rate of 435 ng/kg/min, with an associated period of hypertension. The three branch levels (types I, II and III) were characterized by light microscopy and immunostaining using monoclonal antibodies for proliferating cell nuclear antigen, ED-1 (specific for rat monocytes/macrophages) and α smooth muscle cell (SMC) actin. Cross-sectional areas of the vascular walls were determined morphometrically. In situ hybridizations were performed on paraffin sections using both sense and antisense 35S-labeled cRNA probes generated from rat SMC osteopontin and elastin cDNAs. In the type-I (penetrating) arteries from A-II-infused animals, there was massive fibrinoid necrosis, a marked fibro-proliferative perivascular response, intense monocyte/macrophage infiltration, striking SMC osteopontin and elastin gene expression; SMC, fibroblast and monocyte/macrophage DNA synthesis; and significant increase in the cross-sectional areas of the vascular walls. In the same animals, DNA synthesis also occurred in the larger mesenteric arteries of types II and III where it is associated with significant enlargement of the walls by SMC hypertrophy but without overt morphologic damage. It is suggested that the monocyte/macrophage infiltration and fibroproliferative response of type-I arteries may be related to A-II-induced osteopontin gene expression. Angiotensin infusion in the rat may represent a reproducible model of microvascular injury that can be utilized to elucidate the cellular and molecular biology of a variety of disease states such as hypertension and diabetes mellitus

ISSN:1018-1172    

DOI:10.1159/000159148

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The existence of coronary endoarterial cushions (CEC) in the human heart as nonpathological, functional entities has been debated, and CEC have been sparsely reported in animals. Arterial cushions are localized thickenings that protrude into the lumen of specific arteries. We have identified CEC in the rhesus monkey, dog, sheep, goat, pig, rabbit and rat, and in the human heart. Two distinct types are described: the ovoid CEC arranged singly, in pairs, or in groups of three to four, and the less common polypoid CEC seen primarily in humans. The highest incidence of CEC in rabbits and humans was in the left ventricle in arteries 150–488 µm in diameter. Light and electron microscopy demonstrated intimal location with smooth muscle cells surrounded by ground substance, collagen and elastin fibers in a highly organized pattern. Nerve fibers identified by their immunoreactivity with antiserum to the vasodilatory calcitonin-gene-related peptide contacted the CEC along the tunica media and were occasionally seen within CEC. Arrangement and histological composition of CEC suggest a role in the regulation of local blood flow and myocardial perfusion. In human hearts, the CEC density index correlated highly with the degree of heart disease. In subjects with high heart disease rating, increased connective tissue, lipid-like infiltration and calcification was seen within CEC, and foam cells were present in CEC of obese rabbits. This suggests that CEC in coronary arteries could be predisposed sites of atherosclerosis, and that injured CEC can cause coronary artery spasm and ischemia. We conclude that CEC occur in animals and humans as innervated intimal smooth muscle cushions that might have a role in myocardial perfusion and heart disea

ISSN:1018-1172    

DOI:10.1159/000159149

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The vascular endothelium is the source of a number of vasodilator and vasoconstrictor autacoids and is thus a key regulator of vascular homeostasis. We studied the effects of altering the balance between protein tyrosine kinase and phosphatase activity on Ca2+ signalling and phosphotyrosine levels in cultured human endothelial cells, as well as on autacoid production in native endothelial cells. In isolated segments of rabbit aorta and carotid artery, as well as in bovine coronary arteries, the tyrosine phosphatase inhibitors phenylarsine oxide (PAO) and sodium orthovanadate initiated endothelium-dependent relaxations which could be attributed to the release of nitric oxide and the endothelium-derived hyperpolarizing factor. In cultured endothelial cells incubation with PAO resulted in a time-dependent accumulation in 6-keto prostaglandin F1α, the stable metabolite of prostacyclin, as well as in an increase in the intracellular concentration of free Ca2+ ([Ca2+]i). Inhibition of tyrosine kinases attenuated both the PAO-induced relaxation and the increase in endothelial [Ca2+]i. Western blot analysis of endothelial cells treated with the tyrosine phosphatase inhibitors revealed a time-dependent increase in the tyrosine phosphorylation of a series of bands in both the Triton X-100-soluble and Triton X-100-insoluble (cytoskeletal) fractions. These observations suggest that alterations in cellular levels of phosphotyrosine may have profound effects on vascular homeostasis by modulating Ca2+ signalling and autacoid production in endothelial cells

ISSN:1018-1172    

DOI:10.1159/000159150

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Endothelin (ET)-1 is a potent vasoconstrictor peptide which is also endowed with hypertrophic and mitogenic properties. Enhanced ET-1 gene expression in blood vessels of rats with hypertension induced by deoxycorticosterone acetate (DOCA)-salt has been previously demonstrated. The objective of this study was: (1) to investigate the individual effects of salt and DOCA, and of the development of hypertension in DOCA-salt-hypertensive rats, on ET-1 gene expression in blood vessels; and (2) to correlate the presence of enhanced ET expression and the severity of vascular hypertrophy. By providing salt and/ or DOCA to rats which were or were not unilaterally nephrectomized, groups of rats with variable degrees of blood pressure elevation were generated. Increased abundance of ET-1 mRNA and a greater content of immunoreactive ET-1 were found with progression of hypertension in aorta and the mesenteric arterial bed only in unilaterally nephrectomized DOCA-salt-treated rats (DOCA-salt-hypertensive rats). Vascular expression of ET-1 was not enhanced in other DOCA- or salt-treated rats, even when blood pressure rose to a mean systolic pressure of 180 mm Hg. The wet weight of aorta and the mesenteric arterial bed, the media thickness, the media cross-sectional area, and the media-to-lumen ratio of mesenteric small arteries of all groups of rats exhibited a close correlation with systolic blood pressure. In DOCA-salt-hypertensive rats after 5 weeks, in which overexpression of ET-1 was maximal, the vascular morphometric parameters were excessive for the level of systolic blood pressure. However, in DOCA-salt-hypertensive rats treated with the combined ETA/ETB ET receptor antagonist bosentan, vascular morphometry correlated closely with blood pressure, even though blood pressure was only slightly lower than than of untreated DOCA-salt-hypertensive rats. These data support the hypothesis that ET-1 gene overexpression in blood vessels may accentuate vascular hypertrophy in some forms of hypertension.

ISSN:1018-1172    

DOI:10.1159/000159151

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The effects of endotoxin from Escherichia coli on the vasoconstrictor responses to noradrenaline (10 nM–100 µM) and the thromboxane A2 analog U46619 (100 pM–1 µM) were evaluated on isolated pulmonary and mesenteric arteries from neonatal piglets. Incubation for 20 h with endotoxin (1 µg ml–1) induced a decrease in the contractile responses to noradrenaline in both arteries (p < 0.05) which was inhibited by NG-nitro-L-arginine-methyl ester (L-NAME, 100 µM). Endotoxin-treated mesenteric arteries also showed a reduction of the maximal contractions induced by U46619 (p < 0.05) and this effect was inhibited by L-NAME. In contrast, the contractile responses to U46619 were similar in control and endotoxin-treated pulmonary arteries. In endothelium-denuded pulmonary rings, endotoxin was also unable to modify the contractile responses to U46619. In pulmonary rings, the contractions induced by U46619 (100 nM) were much less sensitive to sodium nitroprus-side, 8-bromo-cyclic GMP or dipyridamole than those induced by 10 µM noradrenaline. In conclusion, endotoxin-treated pulmonary arteries exhibited decreased responses to noradrenaline due to enhanced nitric oxide release but not to the thromboxane A2 analog U46619. This lack of hyporesponsiveness to U46619 in pulmonary arteries may be attributed to a relative insensitivity to nitric oxide. The absence of pulmonary hyporesponsiveness to U46619 may explain why pulmonary hypertension occurs in septic shock despite Ca2+-inde-pendent nitric oxide synthase induction i

ISSN:1018-1172    

DOI:10.1159/000159152

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Erythrocyte lysate increases intracellular Ca2+ ([Ca2+]i)and contracts cerebral arteries in vitro and has been suggested to be the cause for cerebral vasospasm. We investigated the effect of hemolysate on L-type Ca2+ channels directly by using patch clamp techniques in freshly isolated single smooth muscle cells from rat basilar artery. Patch clamp studies revealed a whole-cell current which resembles the L-type Ca2+ current reported by others. Hemolysate reduced the amplitude of the L-type Ca2+ 1 kDa which contains oxyhemoglobin and other proteins mimicked the effect of hemolysate, while the fraction < 1 kDa and ATP were without effect. We conclude that hemolysate does not increase [Ca2+]i by activation of L-type Ca2+ channel.

ISSN:1018-1172    

DOI:10.1159/000159153

出版商:S. Karger AG    

年代:1996

数据来源: Karger