The arterial wall: a new pharmacological and therapeutic target*

Laurent, Stéphane; Vanhoutte, Paul M.; Cavero, Icilio; Chabrier, P.E.; Dupuis, B; Jl, Elghozi; Hamon, Gilles; Janiak, Philip; Juillet, Y; Kher, Archana; Koen, R.; Madonna, O.; Maffrand, J.P.; Pruneau, Didier; Thuillez, Christian

doi:10.1111/j.1472-8206.1996.tb00303.x

Cited by 18 publications

(7 citation statements)

References 84 publications

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“…A central anatomical event in the arterial remodeling associated with the above conditions is the proliferation of local vascular smooth muscle. These mitotic events are stimulated by a variety of circulating hormones and growth factors [7][8][9] and the signaling that leads to this cell proliferation appears to require the activation of a cytosolic phospholipase A 2 (cPLA 2 ) [10,11]. We suggest that some of the pathological effects of Pb 2+ are due to interactions with the Ca 2+ -dependent signaling systems of various hormones and growth factors that involve the activation of cPLA 2 and result in the proliferation of vascular smooth muscle cells (VSMC).…”

Section: Introductionmentioning

confidence: 99%

Lead‐dependent effects on arachidonic acid accumulation and the proliferation of vascular smooth muscle

Dorman¹,

Freeman²

2002

J Biochem & Molecular Tox

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Lead (Pb(2+)) has been implicated in the development of hypertension and atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) is a central feature of both conditions and there is evidence that Pb(2+) potentiates serum-dependent cell growth. The aim of this work was to examine the role of phospholipase A(2) in mitogen-dependent VSMC proliferation and determine if Pb(2+) interacts with this system in order to potentiate mitotic events. It was observed that cell proliferation induced by angiotensin II, or fetal bovine serum, required the activation of a Ca(2+)-dependent cytosolic phospholipase A(2) and the subsequent release of unesterified arachidonic acid. This path was affected by Pb(2+) as the metal increased the amount of arachidonic acid accumulation induced by either mitogen. In addition, Pb(2+) potentiated mitogen-induced DNA synthesis when present at lower doses (0.02 or 0.2 mg%), but had no effect on DNA synthesis, or cell numbers, in unstimulated cells. However, a high dose (2 mg%) of Pb(2+) attenuated the DNA synthesis stimulated by angiotensin II, or serum, but induced the accumulation of unesterified arachidonic acid in unstimulated cells. A biphasic effect of Pb(2+) on cell numbers and viability was also observed as 0.02 or 0.2 mg% Pb(2+) did not affect cell numbers or trypan blue exclusion in unstimulated cells, while 2 mg% Pb(2+) reduced cell numbers and viability. It appeared, therefore, that the lower concentrations of Pb(2+) increased arachidonic acid release and DNA synthesis only in stimulated VSMC, perhaps due to further activation of a Ca(2+)-dependent processes. In contrast, the high dose of Pb(2+) reduced DNA synthesis in stimulated cells and reduced cell numbers and viability in unstimulated cells, which may relate to the noted increase in unesterified arachidonic acid.

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Section: Introductionmentioning

confidence: 99%

Lead‐dependent effects on arachidonic acid accumulation and the proliferation of vascular smooth muscle

Dorman¹,

Freeman²

2002

J Biochem & Molecular Tox

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“…13 In contrast, large arteries undergo mainly hypertrophic remodeling, because their lumen size is generally not reduced, and wall thickness increases in an effort to compensate for the increased wall stress. 10,14 Chronic inhibition of NO synthesis with N G -nitro-Larginine methyl ester (L-NAME) leads to hypertension. Interestingly, in this model, small arteries undergo eutrophic remodeling in proportion to the elevation of arterial pressure.…”

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confidence: 99%

“…6,8 In hypertension, arteries adapt to the pressure-induced elevation in wall stress by changing their geometry. 9,10 Indeed, the elevated vascular resistance observed in hypertension is associated with an increased media thicknesslumen diameter ratio (remodeling) of resistance arteries. 11,12 In essential hypertension, the amount of material in the vessel wall is not augmented but appears to be rearranged around a smaller lumen, and the process has been called eutrophic remodeling.…”

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confidence: 99%

Vessel-Specific Stimulation of Protein Synthesis by Nitric Oxide Synthase Inhibition

et al. 2002

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Abstract-Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [ 3 H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction. Key Words: hypertrophy Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ kinase Ⅲ arteries Ⅲ aorta T he endothelium is an important modulator of vascular reactivity and structure, and NO is one of the main products synthesized and released by endothelial cells. 1 Most of the biological effects of NO are mediated by cGMP and include regulation of vascular tone and endothelial permeability, inhibition of platelet adhesion and aggregation, and inhibition of leukocyte-endothelial cell interactions. 2 In addition, early studies in vascular smooth muscle cells (VSMCs) in culture have shown that NO donors inhibit cellular proliferation 3,4 (for review, see Sarkar and Webb 5 and Jeremy et al 6 ), which is an important event in the pathogenesis of atherosclerosis, restenosis, and possibly hypertension. 7 Among the signaling pathways related to NO inhibition of cell proliferation, inhibition of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation has been proposed to be important, considering the pivotal role of this signaling event in VSMC growth. 6,8 In hypertension, arteries adapt to the pressure-induced elevation in wall stress by changing their geometry. 9,10 Indeed, the elevated vascular resistance observed in hypertension is associated with an increased media thicknesslumen diameter ratio (remodeling) of resistance arteries. 11,12 In essenti...

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“…In atherosclerosis, the arterial neo-intima is the location of the formation of atherosclerotic plaques whereas CAVD disease commences within the boundaries of the valve and ultimately forces an expansion of the valve tissue [13]. Also, angiotensin receptors are expressed in VSMCs in the wall of normal vessels [14] but are not expressed by aortic valve myofibroblasts (avMs) in normal aortic valves [8].…”

Section: Introductionmentioning

confidence: 99%