Nitric Oxide as a Signaling Molecule in the Vascular System: An Overview

Ignarro, Louis J.; Cirino, Giuseppe; Casini, Alessandro; Napoli, Claudio

doi:10.1097/00005344-199912000-00016

Cited by 983 publications

(882 citation statements)

References 85 publications

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“…The reactive oxygen molecule hydrogen peroxide (H 2 O 2 ), the end product of enzymatic conversion of O 2 -by superoxide dismutase (SOD), is also important in the regulation of HIF1 (REFS 28,30). Nitric oxide (NO), also a free radical, is a multifunctional biological gas that is an important cell signalling molecule at low concentrations but can be cytotoxic at high concentrations 31,32 . There are three isoforms of nitric oxide synthase that produce NO from l-arginine 33 .…”

Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…46,47 NO induces relaxation in blood-vessel smooth muscle, thereby promoting vasodilation, whereas a reduction in the availability of NO diminishes capacity for blood vessels to dilate appropriately and favours their constriction and increased blood pressure. 1,3,8 L-arginine is the primary substrate for the generation of NO 4 --6 and has been reported to enhance kidney function, including the excretion of urea, via the generation Abbreviations: ADMA, asymmetric dimethylarginine; Cw, arterial compliance; DBP, diastolic blood pressure; ROS, reactive oxygen species; SBP, systolic blood pressure; SDMA, symmetric dimethylarginine.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-specific differences in L-arginine status in South African men

et al. 2011

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The aetiology for an increasing incidence of hypertensive cardiovascular disease amongst Africans in southern Africa is unclear. Hypertension may be induced by inadequate release of L-arginine-derived nitric oxide impairing vascular tone regulation. In addition, asymmetric dimethylarginine (ADMA) is associated with cardiovascular disease. We compared profiles of L-arginine in African and Caucasian men of similar age with cardiovascular risk factors. We studied 163 Caucasian and 132 African men, respectively, (20 to 70 years) measuring serum L-arginine, ADMA, creatinine, urea, symmetric dimethylarginine (SDMA) and blood pressure. L-arginine levels were significantly lower, whereas blood pressure and pulse wave velocity were significantly higher in African men. Simple linear regression showed ADMA more strongly associated with L-arginine in Caucasians (r ¼ 0.59 vs 0.19), whereas association of SDMA with L-arginine was significant only in Caucasians (r ¼ 0.43 vs 0.001). The stronger association of L-arginine with ADMA in Caucasian men was confirmed by multiple regression analysis (b ¼ 0.46 vs 0.25). Our findings show that the relationship of cardiovascular risk factors with serum L-arginine and some of its catabolites is different in African and Caucasian men and that this may be associated with a relatively higher prevalence of hypertension in African men.

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“…The major sources of O 2 À in cardiovascular cells are: NADH/NADPH oxidase [Griendling et al, 2000], which transfers electrons from NADH or NADPH to molecular oxygen, producing O 2 À ; xanthine oxidase [Wolin, 1996]; endothelial nitric oxide synthase [Ignarro et al, 1999]; cyclooxygenase-2 [Adeagbo et al, 2003]; myeloperoxidase [Berliner and Heinecke, 1996]; and lipoxygenases [Kunsch and Medford, 1999]. The O 2 À that is generated via any of these pathways is converted by superoxide dismutase to H 2 O 2 , which is scavenged by catalase or by peroxidases.…”

Section: Oxidative Stress and Diabetesmentioning

confidence: 99%

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

Joshua

Zhang

Falcone

et al. 2005

J of Cellular Biochemistry

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Complications associated with insulin-dependent diabetes mellitus (type-1diabetes) primarily represent vascular dysfunction that has its origin in the endothelium. While many of the vascular changes are more accountable in the late stages of type-1diabetes, changes that occur in the early or initial functional stages of this disease may precipitate these later complications. The early stages of type-1diabetes are characterized by a diminished production of both insulin and C-peptide with a significant hyperglycemia. During the last decade numerous speculations and theories have been developed to try to explain the mechanisms responsible for the selective changes in vascular reactivity and/or tone and the vascular permeability changes that characterize the development of type-1diabetes. Much of this research has suggested that hyperglycemia and/or the lack of insulin may mediate the observed functional changes in both endothelial cells and vascular smooth muscle. Recent studies suggest several possible mechanisms that might be involved in the observed decreases in vascular nitric oxide (NO) availability with the development of type-1 diabetes. In addition more recent studies have indicated a direct role for both endogenous insulin and C-peptide in the amelioration of the observed endothelial dysfunction. These results suggest a synergistic action between insulin and C-peptide that facilitates increase NO availability and may suggest new clinical treatment modalities for type-1 diabetes mellitus.

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Nitric Oxide as a Signaling Molecule in the Vascular System: An Overview

Cited by 983 publications

References 85 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Ethnicity-specific differences in L-arginine status in South African men

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

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