Physiological mechanisms regulating the expression of endothelial-type NO synthase

Li, Huige; Wallerath, Thomas; Förstermann, Ulrich

doi:10.1016/s1089-8603(02)00127-1

Cited by 203 publications

(157 citation statements)

References 162 publications

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“…Although originally identified as constitutively expressed in endothelial cells, it is becoming clear that eNOS protein can be up-or down-regulated by various extracellular stimuli distinctly via one or more signaling pathways according to cell type and its origin [28]. Activation of ERK2/1 was required for eNOS upregulation by estrogen, angiotensin II, laminar shear stress and mechanical strain [13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

et al. 2008

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Fibroblast growth factor (FGF2), but not vascular endothelial growth factor (VEGF), upregulates endothelial nitric oxide synthase (eNOS) protein expression, at least in part, via activation of extracellular signal-regulated kinase 2/1 (ERK2/1) in ovine fetoplacental artery endothelial (oFPAE) cells. Herein we further investigated the temporal effects of FGF2 and VEGF on other signaling pathways including members (Jun N-terminal kinase JNK1/2 and p38MAPK) of mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog 1 (PI3K/AKT1), and the tyrosine kinase c-SRC, and examined if either one or more of these pathways play a role in the differential regulation of eNOS by FGF2 and VEGF. We first confirmed that in oFPAE cells, FGF2, but not VEGF, increased eNOS protein. FGF2 stimulated eNOS protein in a time and concentration dependent manner, which also depended on cell density. FGF2 provoked sustained (5 min to 12 h) whereas VEGF only stimulated transient (5 min) ERK2/1 phosphorylation. FGF2 was 1.7-fold more potent in stimulating ERK2/1 phosphorylation than VEGF. FGF2 and VEGF only transiently activated JNK1/2 and AKT1 within 5 min; however, FGF2 was a stronger stimulus than VEGF. FGF2 and VEGF did not significantly activate p38MAPK at 5 min; however, VEGF stimulated p38MAPK phosphorylation at 60 min. VEGF but not FGF2 significantly stimulated c-SRC phosphorylation. Inhibitors of MEK-ERK2/1 (PD98059), JNK1/2 (SP600125) and PI3K (wortmannin), but not p38MAPK (SB203580) and SRC (PP2), decreased the FGF2-increased eNOS protein expression. Thus, the FGF2-induced eNOS protein expression requires activation of multiple signaling pathways including ERK2/1, JNK1/2 and PI3K/AKT1. Differences in intensity and temporal patterns of activation of these pathways by FGF2 and VEGF may account for their differential effects on eNOS expression in OFPAE cells.

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Section: Discussionmentioning

confidence: 99%

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

et al. 2008

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“…An alternative interpretation for their findings could be considered. Given the pattern of expression of eNOS, which is regulated not only at the transcriptional level but also posttranscriptionally (25), it is possible that complex interactions between different endogenous mediators released acutely during exercise constitute the stimulus for several chronic adaptations. High-intensity exercise, as used in the above-mentioned study of Miyauchi et al (34), elicits the release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1␤, and IL-6 (35,40,56).…”

Section: Exercise Training and Renal Vascular Reactivitymentioning

confidence: 99%

“…High-intensity exercise, as used in the above-mentioned study of Miyauchi et al (34), elicits the release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1␤, and IL-6 (35,40,56). Interestingly, it has been shown that TNF-␣ induces a downregulation of eNOS, which results from a destabilization of eNOS mRNA with no effect on transcription (25,60). Morever, TNF-␣ release has been shown to increase plasma levels of ET-1 (6,18,58).…”

Section: Exercise Training and Renal Vascular Reactivitymentioning

confidence: 99%

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits

Moraes¹,

Gioseffi²,

Nóbrega³

et al. 2004

Journal of Applied Physiology

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is known to improve vasodilating mechanisms mediated by endothelium-dependent relaxing factors in the cardiac and skeletal muscle vascular beds. However, the effects of exercise training on visceral vascular reactivity, including the renal circulation, are still unclear. We used the experimental model of the isolated perfused rabbit kidney, which involves both the renal macro-and microcirculation, to test the hypothesis that exercise training improves vasodilator mechanisms in the entire renal circulation. New Zealand White rabbits were pen confined (Sed; n ϭ 24) or treadmill trained (0% grade) for 5 days/wk at a speed of 18 m/min during 60 min over a 12-wk period (ExT; n ϭ 24). Kidneys isolated from Sed and ExT rabbits were continuously perfused in a nonrecirculating system under conditions of constant flow and precontracted with norepinephrine (NE). We assessed the effects of exercise training on renal vascular reactivity using endothelial-dependent [acetylcholine (ACh) and bradykinin (BK)] and -independent [sodium nitroprusside (SNP)] vasodilators. ACh induced marked and dose-related vasodilator responses in kidneys from Sed rabbits, the reduction in perfusion pressure reaching 41 Ϯ 8% (n ϭ 6; P Ͻ 0.05). In the kidneys from ExT rabbits, vasodilation induced by ACh was significantly enhanced to 54 Ϯ 6% (n ϭ 6; P Ͻ 0.05). In contrast, BK-induced renal vasodilation was not enhanced by training [19 Ϯ 8 and 13 Ϯ 4% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n ϭ 6; P Ͼ 0.05)]. Continuous perfusion of isolated kidneys from ExT animals with N -nitro-L-arginine methyl ester (L-NAME; 300 M), an inhibitor of nitric oxide (NO) biosynthesis, completely blunted the additional vasodilation elicited by ACh [reduction in perfusion pressure of 54 Ϯ 6 and 38 Ϯ 5% for ExT and L-NAME ϩ ExT, respectively (n ϭ 6; P Ͻ 0.05)]. On the other hand, L-NAME infusion did not affect ACh-induced vasodilation in Sed animals. Exercise training also increased renal vasodilation induced by SNP [36 Ϯ 7 and 45 Ϯ 10% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n ϭ 6; P Ͻ 0.05)]. It is concluded that exercise training alters the rabbit kidney vascular reactivity, enhancing endothelium-dependent and -independent renal vasodilation. This effect seems to be related not only to an increased bioavailability of NO but also to the enhanced responsiveness of the renal vascular smooth muscle to NO. chronic exercise; endothelial dysfunction; isolated perfused rabbit kidney IT IS WELL KNOWN THAT THE endothelium plays a role of paramount importance in the regulation of the vasomotor tone (for review, see Ref. 26). The endothelial cells synthesize and release several relaxing and contracting diffusible substances that interact with the underlying vascular smooth muscle, thus contributing to the continuous modulation of vascular reactivity (26). The best-characterized endothelium-derived relaxing factors are nitric oxide (NO) and prostacyclin (PGI 2 ), which can be released by physical (shear stress by the fl...

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“…The endothelium modulates arterial tone by the release of and/or stimulation of powerful vasodilating and vasoconstricting factors, principally nitric oxide (NO), prostacyclin and endothelium derived hyperpolarising factor (Furchgott & Zawadzki, 1980;Mombouli & Vanhoutte, 1999;Feletou & Vanhoutte, 2009). NO is a powerful vasodilator and is synthesised via nitric oxide synthase (NOS) of which three forms exist; endothelial NOS (eNOS) primarily from endothelial cells; neuronal NOS (nNOS) which is expressed in peripheral nitrergic nerves innervating smooth muscle and also reported in aortic VSMCs; and inducible NOS (iNOS)-the source of which is not clear in the vasculature ( (Forstermann et al, 1995;Furchgott & Zawadzki, 1980); H. (Schwarz et al, 1999;Li et al, 2002)). NO induces dilation via activation of cyclic guanosine monophosphate (cGMP)-mediated pathways (Waldman & Murad, 1987;Bolotina et al, 1994;Ignarro, 2002).…”

Section: Arterial Contractility and Hypertensionmentioning

confidence: 99%

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

Little

Cartwright

Neyses

et al. 2016

Pharmacology & Therapeutics

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The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1, encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP.

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Physiological mechanisms regulating the expression of endothelial-type NO synthase

Cited by 203 publications

References 162 publications

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

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