ReviewPhysiological mechanisms regulating the expression of endothelial-type NO synthase
Section snippets
Expression pattern of eNOS
eNOS was first identified and isolated from bovine aortic endothelial cells [3], [4]. Immunohistochemical studies with a specific antibody to eNOS located the enzyme to various types of endothelial cells (arterial and venous) in many tissues, including human tissues [5]. In addition, eNOS expression has been demonstrated in several nonendothelial cell types and tissues (see Table 1).
Chromosomal localization, genomic structure, and cDNA of eNOS
The human eNOS mRNA is encoded by 26 exons spanning 21–22 kb of genomic DNA [6], [7], [8], [9]. The gene is present as a single copy in the haploid human genome. The human eNOS gene has been assigned to the 7q35→q36 region of chromosome 7 [6], [9]. The bovine eNOS gene spans approximately 20 kb of DNA and also contains 26 exons. Two transcription start sites have been determined which are located 170 and 240 base pairs upstream of the methionine translation initiation codon [10].
Full-length NOS
The cardiovascular phenotype of the eNOS knockout mice
To study the role of eNOS in cardiovascular function, eNOS knockout mice have been generated in several laboratories [18], [19], [20]. All eNOS knockout mice are hypertensive and lack NO-mediated, endothelium-dependent vasodilation [18], [20]. This is strong evidence that endothelial NO is an important systemic vasodilator. In global and focal cerebral ischemia models, eNOS knockout mice demonstrated increased susceptibility to stroke, indicating vascular protective effects of eNOS-derived NO
Characterization of the eNOS promoter
Analyses of the 5′-flanking genomic region of human eNOS demonstrated that the promoter contains no TATA box. The promoter exhibits proximal elements such as Sp1 and GATA motifs consistent with a constitutively expressed gene [30], [31] (Fig. 1). Furthermore, the human eNOS promoter exhibits homologies to numerous binding sites for transcription factors such as AP-1, AP-2, ETS, MAZ, NF-1, NF-IL6, NF-κB, p53, PEA3, and YY1, as well as CACCC-, CCAAT-, heavy metal-, acute-phase response-, shear
Regulation of eNOS mRNA stability
eNOS expression is regulated not only at the transcriptional level, but also posttranscriptionally. The stability of the eNOS mRNA can be altered by different compounds and stimuli. These include TNFα [15], [42], LPS [43], statins [44], thrombin [45], Rho GTPases [46], actin cytoskeleton [47], VEGF [48], oxLDL [49], amphotericin B [50], albumin-derived advanced glycosylation end products [51], glucocorticoids [35], hypoxia [52], and the proliferation status of the cells [53].
TNFα downregulates
Specific regulation of eNOS expression
In recent years, multiple compounds and conditions have been described that regulate the expression of the eNOS gene.
Conclusions
The expression of eNOS, although constitutive in endothelial cells and other cell types, is regulated in numerous ways to meet local demand. The array of mechanisms and compounds that control eNOS expression includes biophysical stimuli (such as shear stress, that upregulates eNOS expression and activity), growth factors (such as TGF-β1, FGF, VEGF, or PDGF that usually stimulate eNOS expression), hormones (such as estrogens, insulin, angiotensin II, or endothelin 1, that also increase eNOS
Acknowledgements
Research in the authors' laboratory pertaining to this topic was supported by the Collaborative Research Center SFB 553, Project A1 (to H.L. and U.F.), from the Deutsche Forschungsgemeinschaft.
References (176)
- et al.
Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene
J. Biol. Chem.
(1993) - et al.
Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene
Biochem. Biophys. Res. Commun.
(1994) - et al.
Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene
Genomics
(1994) - et al.
Organization of the bovine gene encoding the endothelial nitric oxide synthase
Biochim. Biophys. Acta
(1994) - et al.
Molecular cloning and characterization of human endothelial nitric oxide synthase
FEBS. Lett.
(1992) - et al.
Cloning and characterization of murine endothelial constitutive nitric oxide synthase
Biochim. Biophys. Acta
(1996) - et al.
Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthase
J. Biol. Chem.
(1992) - et al.
Molecular cloning, characterization and expression of a nitric oxide synthase from porcine pulmonary artery endothelial cells
Comp. Biochem. Physiol.
(1997) Lessons learned from nitric oxide synthase knockout animals
Semin. Perinatol.
(2000)- et al.
Characterization of the human endothelial nitric-oxide synthase promoter
J. Biol. Chem.
(1999)
Transcriptional regulation of endothelial nitric-oxide synthase by lysophosphatidylcholine
J. Biol. Chem.
Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium
J. Biol. Chem.
Endogenous endothelial cell nitric-oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53
J. Biol. Chem.
Transcriptional induction of endothelial nitric oxide gene by cyclosporine A. A role for activator protein-1
J. Biol. Chem.
Characterization of an upstream enhancer region in the promoter of the human endothelial nitric-oxide synthase gene
J. Biol. Chem.
Characterization of the murine endothelial nitric oxide synthase promoter
Biochim. Biophys. Acta
Assembly and characterization of canine heart endothelial nitric oxide synthase cDNA and 5′-flanking sequence by homology (RT-)PCR cloning
Nitric Oxide
Downregulation of endothelial constitutive nitric oxide synthase expression by lipopolysaccharide
Biochem. Biophys. Res. Commun.
Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase
J. Biol. Chem.
Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase
J. Biol. Chem.
Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins
Atherosclerosis
Expression of an endothelial-type nitric oxide synthase isoform in human neutrophils: Modification by tumor necrosis factor-alpha and during acute myocardial infarction
J. Am. Coll. Cardiol.
Induction of nitric oxide synthase mRNA by shear stress requires intracellular calcium and G-protein signals and is modulated by PI 3 kinase
Biochem. Biophys. Res. Commun.
Increased endogenous nitric oxide production induced by physical exercise in peripheral arterial occlusive disease patients
Life. Sci.
A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells
Biochem Biophys Res Commun
VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR)
Biochem. Biophys. Res. Commun.
Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway
J. Biol. Chem.
Increased expression of endothelial constitutive nitric oxide synthase in rat aorta during pregnancy
Biochem. Biophys. Res. Commun.
Activation of estrogen receptor beta is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes
FEBS Lett.
Coronary artery endothelial protection after local delivery of 17beta-estradiol during balloon angioplasty in a porcine model: a potential new pharmacologic approach to improve endothelial function
J. Am. Coll. Cardiol.
Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta
Arterioscler. Thromb. Vasc. Biol.
Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: Activation by angiotensin II in hypertension
Circ. Res.
Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells
Proc. Natl. Acad. Sci. USA
Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells
Proc. Natl. Acad. Sci. USA
Characterization and localization of endothelial nitric oxide synthase using specific monoclonal antibodies
Am. J. Physiol.
Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene
Eur. J. Biochem.
Endothelial nitric oxide synthase: Molecular cloning and characterization of a distinct constitutive enzyme isoform
Proc. Natl. Acad. Sci. USA
Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase
J. Clin. Invest.
Hypertension in mice lacking the gene for endothelial nitric oxide synthase
Nature
Limb reduction defects in endothelial nitric oxide synthase-deficient mice
Am. J. Physiol. Heart. Circ. Physiol.
Inotropic response to beta-adrenergic receptor stimulation and anti-adrenergic effect of ACh in endothelial NO synthase-deficient mouse hearts
J. Physiol.
Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-l-arginine
J. Cereb. Blood. Flow. Metab.
Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice
J. Clin. Invest.
Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling
J. Clin. Invest.
The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia
J. Clin. Invest.
Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene
Circ. Res.
Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3
J. Clin. Invest.
Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase: Contributions of NOS isoforms to blood pressure and heart rate control
Cardiovasc. Res.
Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene
Circulation
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