Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells

Phelan, Michael W.; Faller, Douglas V.

doi:10.1002/(sici)1097-4652(199606)167:3<469::aid-jcp11>3.0.co;2-#

Cited by 110 publications

(20 citation statements)

References 43 publications

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“…Previous studies of NOS expression in systemic and pulmonary endothelial cells from different species in cultures [31,32,33,34,35,36,37] have yielded conflicting results. Recently, Toporsian et al [38] reported in vivo downregulation of eNOS mRNA and protein levels in the aorta of rats following prolonged hypoxia, which correlated with impaired endothelium-dependent vasorelaxation, whereas there was an increase in eNOS protein levels in the lungs.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension

et al. 2001

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BackgroundThe importance of nitric oxide (NO) in hypoxic pulmonary hypertension has been demonstrated using nitric oxide synthase (NOS) knockout mice. In that model NO from endothelial NOS (eNOS) plays a central role in modulating pulmonary vascular tone and attenuating hypoxic pulmonary hypertension. However, the normal regulation of NOS expression in mice following hypoxia is uncertain. Because genetically engineered mice are often utilized in studies of NO, we conducted the present study to determine how hypoxia alters NOS expression in wild-type mice.MethodMice were exposed to sea level, ambient conditions (5280 feet) or severe altitude (17,000 feet) for 6 weeks from birth, and hemodynamics and lung NOS expression were assessed.ResultsHypoxic mice developed severe pulmonary hypertension (right ventricular systolic pressure [RVsP] 60 mmHg) as compared with normoxic mice (27 mmHg). Using quantitative reverse-transcription PCR, it was found that expressions of eNOS and inducible NOS (iNOS) increased 1.5-fold and 3.5-fold, respectively, in the lung. In addition, the level of lung eNOS protein was increased, neuronal NOS (nNOS) protein was unchanged, and iNOS was below the limit of detection. Immunohistochemistry demonstrated no change in lung iNOS or nNOS staining in either central or peripheral areas, but suggested increased eNOS in the periphery following hypoxia.ConclusionIn mice, hypoxia is associated with increases in lung eNOS, possibly in iNOS, but not in nNOS; this suggests that the pattern of lung NOS expression following hypoxia must be considered in studies using genetically engineered mice.

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Section: Discussionmentioning

confidence: 99%

Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension

et al. 2001

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“…Expression and activity of eNOS, a main source of basal endothelial NO, have been reported to be upregulated (Arnet et al 1996; Le Cras et al 1998; Coulet et al 2003; Shirai et al 2003), downregulated (McQuillan et al 1994; Liao et al 1995; Phelan and Faller 1996; Laufs et al 1997; Toporsian et al 2000; Takemoto et al 2002), or unchanged (Murata et al 2001; Tahawi et al 2007) in various experimental models of hypoxia and repetitive hypoxia/reoxygenation. Contradictory reports of eNOS expression and activity appear to be due to temporal variations in experimental hypoxemic conditions, and differences in the species and vascular bed from which endothelial cells were derived.…”

Section: Repetitive Hypoxia/reoxygenationmentioning

confidence: 99%

Mechanisms of endothelial dysfunction in obstructive sleep apnea

Atkeson

Jelić

2008

VHRM

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Endothelial activation and infl ammation are important mediators of accelerated atherogenesis and consequent increased cardiovascular morbidity in obstructive sleep apnea (OSA). Repetitive episodes of hypoxia/reoxygenation associated with transient cessation of breathing during sleep in OSA resemble ischemia/reperfusion injury and may be the main culprit underlying endothelial dysfunction in OSA. Additional factors such as repetitive arousals resulting in sleep fragmentation and deprivation and individual genetic suseptibility to vascular manifestations of OSA contribute to impaired endothelial function in OSA. The present review focuses on possible mechanisms that underlie endothelial activation and infl ammation in OSA.

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“…Thus, control and regulation of the eNOS enzyme at the cellular level had previously been proposed to be chiefly through activation of specific cell surface receptors by calcium‐mobilizing agonists. However, we recently reported that exposure of endothelial cells to low (but physiological) oxygen tensions ( P O 2 = 20–40 mmHg) results in a profound decrease in the transcript for eNOS and a corresponding fall in eNOS protein levels 50 and co‐ordinate impairment of production of NO in response to stimulators of eNOS. Transition metals inhibited the hypoxic regulation of cNOS transcripts, suggesting a mechanism comparable to that by which oxygen tension regulates expression of other vasoregulatory genes, and new gene transcription is required for eNOS suppression by hypoxia.…”

Section: Vasoactive Genes Regulated By Hypoxiamentioning

confidence: 99%

“…Levels of cyclo‐oxygenase‐2 (COX‐2) mRNA and protein are increased by hypoxia 67 . In addition, hypoxia also decreases endothelial cell expression of genes encoding or producing a number of antimitogenic or antiproliferative agents, including eNOS 16 , 46 , 50 . Hypoxia reduces endothelial cell release of prostacyclin 68 and heparan sulphates, 69 , 70 which inhibit proliferation.…”

Section: Hypoxia and Tissue Remodellingmentioning

confidence: 99%

Endothelial Cell Responses to Hypoxic Stress

Faller

1999

Clin Exp Pharma Physio

327

223

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1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes. 2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue. 3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF-B, endothelin-1, VEGF, thrombospondin-1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP-9), thrombospondin-1) and reciprocal transcriptional inhibition of vasodilatory or anti-mitogenic effectors (eNOS). 4. Oxygen appears to signal through a novel haem-containing sensor and signals initiated by this sensor alter the levels and DNA-binding activity of transcription factors such as activating protein (AP)-1, nuclear factor-kappa B and hypoxia-inducible transcription factor-1. 5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO). 6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types). 7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia. 8. Short-term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer-term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling. 9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short-term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis. 10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).

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Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells

Cited by 110 publications

References 43 publications

Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension

Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension

Mechanisms of endothelial dysfunction in obstructive sleep apnea

Endothelial Cell Responses to Hypoxic Stress

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