Nitric Oxide Protects Against Leukocyte-Endothelium Interactions in the Early Stages of Hypercholesterolemia

Gauthier, Theresa W.; Scalia, Rosario; Murohara, Toyoaki; Guo, Jenny; Lefer, Allan M.

doi:10.1161/01.atv.15.10.1652

Cited by 196 publications

(126 citation statements)

References 32 publications

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“…This finding is of particular interest considering the complex role exerted by nitric oxide in the homeostasis of endothelial cells [18,19] and in the regulation of leukocyte-endothelium interaction [20][21][22]. In this regard, it is well known that an acute decrease in NO production by the vascular endothelium up-regulates endothelial cell adhesion molecule expression (i.e., P-selectin and ICAM-1), thus enhancing leukocyte-endothelial interaction [12,[23][24][25].…”

Section: Discussionmentioning

confidence: 99%

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Scalia

Lefer

1998

Journal of Leukocyte Biology

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Abstract:The relationship between acute endothelial dysfunction and the extravasation of leukocytes was studied in vivo with intravital microscopy of the rat mesenteric microvasculature. Acute endothelial dysfunction of the rat mesenteric microvasculature was induced in vivo by superfusing the mesentery for 90 min with one of three different stimulating agents: N G -nitro-L-arginine methyl ester (L-NAME, 50 µM), thrombin (0.5 U/mL), or hydrogen peroxide (H 2 O 2 , 50 µM). All three agents induced a similar increase in leukocyte rolling and adherence, which was significantly greater than that observed in control rats superfused with KrebsHenseleit solution (P F 0.01). Transendothelial migration of leukocytes into the perivascular space was also increased by superfusion with L-NAME, thrombin, or H 2 O 2 . However, there was a greater increase in the number of migrated leukocytes in the rat mesentery after L-NAME and H 2 O 2 superfusion than that observed during thrombin superfusion. In vivo infusion of a neutralizing antibody against platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically inhibited L-NAMEinduced and H 2 O 2 -induced migration of leukocytes but did not prevent extravasation of leukocytes induced by thrombin. In rat mesenteries superfused with the three different stimuli, immunohistochemical analysis of endothelial cell adhesion molecules expressed on the microvascular endothelium revealed a significant increase of ICAM-1, but not PECAM-1, endothelial cell surface expression (P F 0.01 and P G 0.05 vs. control rats, respectively). Our data confirm a key role for PECAM-1 acutely in leukocyte extravasation in vivo and indicate that the involvement of constitutively expressed PECAM-1 in leukocyte transendothelial migration is preferentially correlated to oxidative stressrelated stimuli in the microvascular endothelium.

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Section: Discussionmentioning

confidence: 99%

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Scalia

Lefer

1998

Journal of Leukocyte Biology

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“…24 Specifically, increased levels of NO are associated with decreased leukocyte adhesion molecule expression. [23][24][25][26] The mechanisms by which NO modulates expression of these adherence molecules is unclear but have been speculated to include NO-dependent regulation of oxidantresponsive transcription via nuclear factor-B (NF-B) 23,26 and/or endothelial cGMP concentrations. [25][26][27][28] Indeed, the addition of 8-bromoguanosine 3Ј,5Ј-cyclic monophosphate (8-Br-cGMP), but not 8-Br-cAMP, after inhibition of endothelial NO synthesis has been shown to reduce both endothelial adhesion molecule expression and leukocyte adherence.…”

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confidence: 99%

“…19 Adhesion molecules regulated by NO include P-selectin, 22 VCAM-1, 23 and ICAM-1. 24 Specifically, increased levels of NO are associated with decreased leukocyte adhesion molecule expression. [23][24][25][26] The mechanisms by which NO modulates expression of these adherence molecules is unclear but have been speculated to include NO-dependent regulation of oxidantresponsive transcription via nuclear factor-B (NF-B) 23,26 and/or endothelial cGMP concentrations.…”

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confidence: 99%

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

Collard¹,

Agah²,

Reenstra³

et al. 1999

ATVB

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Abstract-We have previously shown that reoxygenation of hypoxic human umbilical vein endothelial cells (HUVECs) leads to the activation and deposition of complement. In the present study, we investigated whether the terminal complement complex (C5b-9) influences HUVEC nuclear factor-B (NF-B) translocation and vascular cell adhesion molecule-1 (VCAM-1) protein expression after hypoxia/reoxygenation by decreasing endothelial cGMP. Additionally, we investigated the action of anti-human C5 therapy on endothelial cGMP, NF-B translocation, and VCAM-1 protein expression. Reoxygenation (0.5 to 3 hours, 21% O 2 ) of hypoxic (12 hours, 1% O 2 ) HUVECs in human serum (HS) significantly increased C5b-9 deposition, VCAM-1 expression, and NF-B translocation compared with hypoxic/reoxygenated HUVECs treated with the recombinant human C5 inhibitor h5G1.1-scFv. Acetylcholine (ACh)-induced cGMP synthesis was significantly higher in normoxic HUVECs compared with hypoxic HUVECs reoxygenated in HS but did not differ from hypoxic HUVECs reoxygenated in buffer or HS treated with h5G1.1-scFv. Treatment of hypoxic/reoxygenated HUVECs with h5G1.1-scFv or cGMP analogues significantly attenuated NF-B translocation and VCAM-1 protein expression. Treatment with NO analogues, but not a cAMP analogue, cGMP antagonists, or an NO antagonist, also significantly attenuated VCAM-1 expression. We conclude that (1) C5b-9 deposition, NF-B translocation, and VCAM-1 protein expression are increased in hypoxic HUVECs reoxygenated in HS; (2) reoxygenation of hypoxic HUVECs in HS, but not buffer alone, attenuates ACh-induced cGMP synthesis; and (3) Key Words: adhesion molecules Ⅲ hypoxia Ⅲ inflammation Ⅲ nitric oxide Ⅲ immunotherapy I ncreasing evidence suggests that the terminal complement complex (C5b-9) plays an integral role in the pathogenesis of atherosclerosis 1-5 and vascular injury after ischemiareperfusion, cardiopulmonary bypass, and acute myocardial infarction. 6 -11 In addition to amplifying the local inflammatory response by inducing endothelial interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) secretion, 12 C5b-9 also influences endothelial vascular tone [13][14][15] 16 ). Yet the mechanisms by which C5b-9 influences endothelium-dependent relaxation and leukocyte adhesion molecule expression have not been fully elucidated.Vascular tone and leukocyte adhesion molecule expression can be regulated by NO. 18,19 NO synthesized by the vascular endothelium induces vasodilation by activation of soluble guanylate cyclase and the subsequent increase of cGMP. 20 In addition to being a potent smooth muscle relaxant, NO inhibits platelet aggregation 21 and suppresses endothelial neutrophil adhesion molecule expression. 19 Adhesion molecules regulated by NO include P-selectin, 22 VCAM-1, 23 and ICAM-1. 24 Specifically, increased levels of NO are associated with decreased leukocyte adhesion molecule expression. [23][24][25][26] The mechanisms by which NO modulates expression of these adherence molecules is unclear but have been specul...

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“…Reduced endothelium-dependent vascular relaxation is an early event in atherosclerosis 2,3 ; in addition, NO inhibits many key atherogenic processes, including platelet adhesion and aggregation, 4,5 adhesion molecule and chemokine expression, 6,7 and smooth muscle cell migration and proliferation. 8,9 Thus, early endothelial NO deficiency may promote progression to more advanced vascular lesions.…”

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In Vivo Gene Transfer of Nitric Oxide Synthase Enhances Vasomotor Function in Carotid Arteries From Normal and Cholesterol-Fed Rabbits

et al. 1998

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Background-The vascular endothelium is anatomically intact but functionally abnormal in preatherosclerotic states, and an early deficit in the bioavailability of nitric oxide (NO) or related molecules has been described in both humans and animal models. We hypothesized that the targeted gene transfer of NO synthase (NOS) isoforms might ameliorate or reverse the deficit. Methods and Results-We constructed a recombinant adenovirus, Ad.nNOS, that expresses the neuronal isoform of NOS (nNOS) and used it for in vivo endovascular gene transfer to carotid arteries (CA) from normal and cholesterol-fed rabbits. Vessels were harvested 3 days after gene transfer. In CA from normal rabbits, Ad.nNOS generated high levels of functional nNOS protein predominantly in endothelial cells and increased vascular NOS activity by 3.4-fold relative to sham-infected control CA. Ad.nNOS gene transfer also significantly enhanced endothelium-dependent vascular relaxation to acetylcholine; at 3 mol/L acetylcholine, Ad.nNOS-treated arteries showed an 86Ϯ4% reduction in precontracted tension, whereas control CA showed a 47Ϯ6% reduction in tension. Contraction in response to phenylephrine and relaxation in response to nitroprusside were unaffected in both control and Ad.nNOS-treated CA. To determine the effect of Ad.nNOS in atherosclerotic arteries, 10 male New Zealand White rabbits maintained on a 1% cholesterol diet for 10 to 12 weeks underwent gene transfer according to the same protocol used in normal rabbits. Ad.nNOS-treated arteries showed a 2-fold increase in NADPH-diaphorase staining intensity relative to sham-infected and Ad.␤Gal-treated arteries. The CA from cholesterol-fed rabbits showed impaired acetylcholine-induced relaxation, but this abnormality was almost entirely corrected by Ad.nNOS gene transfer. Conclusions-In vivo adenovirus-mediated endovascular delivery of nNOS markedly enhances vascular NOS activity and can favorably influence endothelial physiology in the intact and atherosclerotic vessel wall.

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Nitric Oxide Protects Against Leukocyte-Endothelium Interactions in the Early Stages of Hypercholesterolemia

Cited by 196 publications

References 32 publications

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

In Vivo Gene Transfer of Nitric Oxide Synthase Enhances Vasomotor Function in Carotid Arteries From Normal and Cholesterol-Fed Rabbits

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