Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

Caterina, Raffaele De; Libby, Peter; Peng, Haibing; Thannickal, Victor J.; Rajavashisth, Tripathi B.; Gimbrone, Michael A.; Shin, Wee Soo; Liao, James K.

doi:10.1172/jci118074

Cited by 1,617 publications

(939 citation statements)

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“…It has been described that nitric oxide (NO), which is produced as a result of VEGFR-2 signaling, 42 represses gene transcription of VCAM-1 in human saphenous vein endothelial cells. 43 This observation suggests that sunitinib may promote endothelial expression of VCAM-1 by inhibiting the repressing function of NO. In contrast, it has been suggested that the NO-dependent pathway is not involved in VEGF-induced mRNA expression of VCAM-1 in human umbilical vein endothelial cells (HUVECS).…”

Section: Discussionmentioning

confidence: 99%

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Veldt

Vroling

Haas

et al. 2011

Intl Journal of Cancer

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Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (q) 5 0.378, p 5 0.028] and vWF (q 5 0.417, p 5 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p 5 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (q 5 0.605; p 5 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.

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Section: Discussionmentioning

confidence: 99%

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Veldt

Vroling

Haas

et al. 2011

Intl Journal of Cancer

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“…Loss of endothelial-derived NO activity leading to reduction in intracellular cGMP levels contributes to impaired vascular responses (Liao et al, 1991), enhanced platelet aggregation (Radomski et al, 1992), and vascular smooth muscle proliferation (Garg and Hassid, 1989). Inhibition of endothelial NO production by the eNOS inhibitor N o -monomethyl-L-arginine (L-NMA) causes vasoconstriction (Kurose et al, 1993), and vascular inflammation by promoting endothelial-leukocyte adhesion (De Caterina et al, 1995). Indeed, lower vascular cGMP levels in mutant mice lacking eNOS are associated with systemic and pulmonary hypertension (Huang et al, 1995;Steudel et al, 1997), greater propensity for intimal smooth muscle proliferation in response to vascular cuff injury (Moroi et al, 1998), and larger stroke sizes in response to cerebral ischemia (Huang et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Kim

Sawada

Soydan

et al. 2008

J Cereb Blood Flow Metab

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Recent studies suggest that dipyridamole (DP) may exert stroke protective effects beyond platelet inhibition. The purpose of this study is to determine whether statin and DP could enhance stroke protection through nitric oxide (NO)-dependent vascular effects. Mice were pretreated with DP (10 to 60 mg/kg, q 12 h, 3 days) alone or in combination with a statin (simvastatin; 0.1 to 20 mg/kg per day, 14 days) before transient intraluminal middle cerebral artery occlusion. Although simvastatin (1 mg/kg per day, 14 days) increased endothelial NO synthase (eNOS) activity by 25% and DP (30 mg/kg, q12 h, 3 days) increased aortic cGMP levels by 55%, neither statin nor DP alone, at these subtherapeutic doses, increased absolute cerebral blood flow (CBF) or conferred stroke protection. However, the combination of subtherapeutic doses of simvastatin and DP increased CBF by 50%, decreased stroke volume by 54%, and improved neurologic motor deficits, all of which were absent in eNOS-deficient mice. In contrast, treatment with aspirin (10 mg/kg per day, 3 days) did not augment the neuroprotective effects of DP and/or simvastatin. These findings indicate that statin and DP exert additive NO-dependent vascular effects and suggest that the combination of statin and DP has greater benefits in stroke protection than statin alone through vascular protection.

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“…The molecular mechanisms are mainly calcium-independent [20] and involve posttranslational modification by phosphorylation of eNOS at regulatory sites [21], messenger RNA (mRNA) stabilization [22], e.g., through heat shock protein 90 (hsp-90), and translocation [23]. NO produced in response to shear stress triggers vascular smooth muscle relaxation, inhibition of apoptosis [24], and inhibition of thrombocyte or monocyte adhesion [25]. Repeated transient shear stress induces NOS3 (eNOS gene) transcription and leads thus to chronically higher NO production in response to stimuli.…”

Section: Introductionmentioning

confidence: 99%

Endothelial dysfunction in cardiovascular disease and Flammer syndrome—similarities and differences

et al. 2017

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The endothelium has increasingly been recognized as a smart barrier and a key regulator of blood flow in microand macrovascular beds. Endothelial dysfunction marks a stage of atherosclerosis and is an important prognostic marker for cardiovascular disease. Yet, some people who tend to be slim and physically active and with rather low blood pressure show a propensity to respond to certain stimuli such as emotional stress with endothelial-mediated vascular dysregulation (Flammer syndrome). This leads to characteristic vascular symptoms such as cold hands but also a risk for vascularmediated diseases such as normal-tension glaucoma. It is the aim of this review to delineate the differences between Flammer syndrome and its Bcounterpart^endothelial dysfunction in the context of cardiovascular diseases.

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Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

Abstract: IntroductionTo Invest. 1995. 96:60-68.)

Cited by 1,617 publications

References 42 publications

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Endothelial dysfunction in cardiovascular disease and Flammer syndrome—similarities and differences

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