Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Background Strain C57BL/6J Donor Strain 129P2 via E14TG2a ES cell line Generation N12F19 (03-JAN-08)   Donating Investigator Oliver Smithies,   University of North Carolina

Appearance
black
Related Genotype: a/a

Description
Mice homozygous for the Nos3^tm1Unc targeted mutation are viable and fertile. They have elevated blood pressure that is about 20 mmHg higher than that seen in normal wildtype siblings. They also show a decreased heart rate. Female homozygotes are smaller in body weight than normal wildtype siblings. Hyperglycemic-euglycemic clamp studies demonstrate that homozygotes exhibit insulin resistance at the level of the liver and peripheral tissues.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to replace 129 bp of exon 12, which disrupted the calmodulin binding domain. The construct was electroporated into 129P2/OlaHsd-derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were crossed to C57BL/6 female mice. Heterozygotes were intercrossed to generate homozygotes. The mice were subsequently backcrossed onto the C57BL/6J background for 12 generations.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Nos3^tm1Unc allele

007073

CByJ.129P2(B6)-Nos3tm1Unc/J

View Strains carrying   Nos3^tm1Unc     (1 strain)

Additional Web Information

Congenic Nomenclature
Genetic Quality Control Annual Report

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Aortic Valve Disease - Models with phenotypic similarity to human disease where etiologies are distinct.2
	Hypertension, Essential - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Pulmonary Hypertension, Familial Persistent, of the Newborn - Models with phenotypic similarity to human disease where etiologies are distinct.2

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s). 2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Nos3^tm1Unc/Nos3^tm1Unc

        B6.129P2-Nos3^tm1Unc/J

• lethality-prenatal/perinatal
• neonatal lethality (MGI Ref ID J:98913)
  • about 40% die within the first hour of birth
• growth/size phenotype
• fetal growth retardation (MGI Ref ID J:98913)
  • fetuses from E18 to term demonstrate slight growth retardation
• cardiovascular system phenotype
• abnormal angiogenesis (MGI Ref ID J:98913)
  • impaired pulmonary angiogenesis
  • occasionally exhibit misalignment of pulmonary veins, which are seen in anomalous locations adjacent to the lung pleura, running alongside arterial vessels and sharing a common adventitial sheath
• abnormal vascular branching morphogenesis (MGI Ref ID J:98913)
  • E19.5 lungs show dramatic decrease of arteriolar branches and regions of marked capillary hypoperfusion
• abnormal aortic valve morphology (MGI Ref ID J:103340)
  • high incidence (5 of 12) bicuspid aortic valves, however do not exhibit aortic coarctation
• abnormal lung vasculature (MGI Ref ID J:98913)
  • abnormalities in pulmonary vascular development
  • disorganization of the extracellular matrix structure in the lung vasculature
  • capillaries of preterm mice remain deep within thickened septae, instead of aligning with the saccular epithelium, resulting in significantly fewer capillaries abutting saccular airspaces
• cardiac hypertrophy (MGI Ref ID J:98094)
  • homozygotes show no significant differences in baseline heart weight or myocyte size relative to wild-type mice
  • however, in response to transverse aortic constriction (TAC)-induced pressure overload, wild-type hearts exhibit a progressive cardiac hypertrophy with significant dilatory remodeling whereas mutant hearts show more modest and concentric cardiac hypertrophy at 3 weeks, with minimal further progression
  • at 9 weeks after TAC, mutant hearts develop significantly less intestitial fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and alpha-skeletal actin) relative wild-type hearts
• increased left ventricle systolic pressure (MGI Ref ID J:98094)
  • in response to TAC-induced pressure overload, homozygotes exhibit a similar or greater rise in LV systolic pressure and ventricular afterload (arterial elastance [Ea]) at 9 weeks relative to wild-type mice
• increased ventricle muscle contractility (MGI Ref ID J:98094)
  • at 9 weeks of TAC, wild-type hearts exhibit a rightward shift of LV pressure-volume (PV) loops and end-systolic and end-diastolic PV relations reflecting remodeling; in contrast, mutant hearts display a leftward shift with smaller end-diastolic and end-systolic chamber volumes, as well as preserved wall thickness and fractional shortening, indicating preserved or enhanced systolic and diastolic function
• lung hemorrhage (MGI Ref ID J:98913)
  • E16 lungs show scattered areas of parenchymal and interlobar hemorrhages
• respiratory system phenotype
• abnormal lung morphology (MGI Ref ID J:98913)
  • fetal lungs demonstrate abnormally compact lung structure and lungs of pups show evidence of septal thickening and reduced airspaces
  • E20 lungs display absence of discernible basement membrane in the distal airways
  • exhibit a decrease in apoptosis in the lungs
  • E16 lungs display scattered subpleural hematomas
• abnormal lung vasculature (MGI Ref ID J:98913)
  • abnormalities in pulmonary vascular development
  • disorganization of the extracellular matrix structure in the lung vasculature
  • capillaries of preterm mice remain deep within thickened septae, instead of aligning with the saccular epithelium, resulting in significantly fewer capillaries abutting saccular airspaces
• abnormal type II pneumocyte morphology (MGI Ref ID J:98913)
  • do not show evidence of lamellar bodies
  • observe an increase in markedly swollen glycogen laden pneumocytes protruding into airspaces compared to wild-type
• thick alveolar septum (MGI Ref ID J:98913)
  • pups exhibit marked septal thickening
• abnormal production of surfactant (MGI Ref ID J:103340)
  • preterm and newborn lungs often display an absence of recognizable surfactant material within the airspaces
• abnormal surfactant secretion (MGI Ref ID J:103340)
  • lack of surfactant in bronchial alveolar lavage fluid
• lung hemorrhage (MGI Ref ID J:98913)
  • E16 lungs show scattered areas of parenchymal and interlobar hemorrhages
• respiratory distress (MGI Ref ID J:98913)
  • some newborns exhibit severe respiratory distress
• homeostasis/metabolism phenotype
• cyanosis (MGI Ref ID J:98913)
  • some newborns show varying levels of cyanosis
• muscle phenotype
• increased ventricle muscle contractility (MGI Ref ID J:98094)
  • at 9 weeks of TAC, wild-type hearts exhibit a rightward shift of LV pressure-volume (PV) loops and end-systolic and end-diastolic PV relations reflecting remodeling; in contrast, mutant hearts display a leftward shift with smaller end-diastolic and end-systolic chamber volumes, as well as preserved wall thickness and fractional shortening, indicating preserved or enhanced systolic and diastolic function
• cellular phenotype
• abnormal redox activity (MGI Ref ID J:98094)
  • in response to TAC-induced pressure overload, homozygotes (but not wild-type mice) exhibit blunted myocardial ROS generation and blunted nitrotyrosine, and gelatinase zymogen activity with no significant decline in the GSH/GSSH or NADPH/NADP ratio

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Nos3^tm1Unc/Nos3⁺

        involves: 129P2/OlaHsd * C57BL/6J

• cardiovascular system phenotype
• increased vasodilation (MGI Ref ID J:54772)
  • aortic rings isolated from normotensive heterozygous mutant mice show normal endothelium-dependent vasorelaxation induced by acetylcholine and the calcium ionophore A23187
  • however, vasorelaxations to the endothelium-independent vasodilator nitroglycerin are modestly enhanced in heterozygous aortic rings relative to wild-type

Nos3^tm1Unc/Nos3^tm1Unc

        involves: 129P2/OlaHsd * C57BL/6

• life span-post-weaning/aging
• abnormal induced morbidity/mortality (MGI Ref ID J:113106)
  • after injection of platelet-activating factor (PAF), <10% mortality occurs within 30 minutes
  • pretreatment with wortmannin before PAF treatment confers 100% protection to mutants and wild type pretreatment with wortmannin before PAF treatment confers 100% protection to mutants and wild-type
  • in BSA-induced anaphylaxis, all mutants survive compared to fatality in 82% of controls; in OVA model, 92% of control mice die but all mutants survive challenge
• growth/size phenotype
• decreased body weight (MGI Ref ID J:36559)
  • body weights at 14 weeks of age are approximately 7.5% lower than in wild-type
• homeostasis/metabolism phenotype
• decreased body temperature (MGI Ref ID J:113106)
  • challenge with BSA 2 weeks after sensitization with BSA induces severe hypothermia and mice succumb to systemic shock reaction; mutants show no mortality and only a delayed, mild, transient hypothermia
  • similar results are seen with OVA-induced anaphylaxis
• increased circulating renin level (MGI Ref ID J:36559)
  • plasma renin concentrations are nearly twice as high as in wild-type
• cardiovascular system phenotype
• decreased heart rate (MGI Ref ID J:36559)
  • 670 beats per min vs. 709 beats per min in wild-type
• decreased vascular permeability (MGI Ref ID J:113106)
  • in BSA/BSA model of anaphylaxis, vascular permeability increased significantly in wild-type but very little in mutants; vascular leakage (extravasation) of Evans Blue dye (EB) is 2-fold lower than in wild-type mice
  • in OVA/OVA model, no vascular permeability increase occurs in mutants and extravasation is significantly lower than in wild-type
• increased blood pressure (MGI Ref ID J:36559)
• immune system phenotype
• *normal* immune system phenotype (MGI Ref ID J:36559)
  • exhibit a similar susceptibility to lipopolysaccharide-induced death as wild type exhibit a similar susceptibility to lipopolysaccharide-induced death as wild-type

Nos3^tm1Unc/Nos3^tm1Unc

        involves: 129P2/OlaHsd

• life span-post-weaning/aging
• premature death (MGI Ref ID J:102136)
  • 50% of males die by 21 months of age, however female survival is similar to wild-type
• growth/size phenotype
• decreased body weight (MGI Ref ID J:102136)
  • both males and females weight less than wild-type at 21 months of age
• cardiovascular system phenotype
• abnormal blood pressure (MGI Ref ID J:102136)
• increased blood pressure (MGI Ref ID J:102136)
  • mean blood pressure is significantly elevated in both males and females at 5.5 months of age
  • at 21 months of age, females, but not males, continue to exhibit increased mean blood pressure
• hypertension (MGI Ref ID J:103153)
  • arterial hypertension
  • females are hypertensive at 7 months of age and maintain the elevated pressure at 21 months of age, however do not exhibit any contractile dysfunction
• increased diastolic blood pressure (MGI Ref ID J:102136)
  • elevated at 5.5 months of age in both males and females
  • at 21 months of age, females, but not males, continue to exhibit an increased diastolic blood pressure
• increased systolic blood pressure (MGI Ref ID J:102136)
  • elevated at 5.5 months of age in both males and females
  • at 21 months of age, females, but not males, continue to exhibit an increased systolic blood pressure
• abnormal heart morphology (MGI Ref ID J:102136)
  • at 21 months of age, males exhibit wall thinning of the heart while females display an increase in wall thickness of the heart
• abnormal ventricular septum morphology (MGI Ref ID J:102136)
  • females, but not males, exhibit a significant increase in diastolic septal wall thickness and to a lesser degree in the posterior wall
  • males exhibit a decrease in interventricular septum thickening at 21 months of age
• cardiac hypertrophy (MGI Ref ID J:102136)
  • at 21 months of age, males have a large increase and females have a slight increase in heart size
• dilated left ventricle (MGI Ref ID J:102136)
  • left-ventricular end-systolic chamber dilation (LVESD) is increased about 45% in homozygous males compared to 25% in wild-type males at 21 months of age; no differences seen in females
  • left ventricular mass (LVMASS) is increased in both males and females at 21 months of age
  • ratio between LVMASS and LV volume is increased in 21 month old males
• increased heart weight (MGI Ref ID J:102136)
  • large increase in heart weight and heart weight to body weight ratio in males at 21 months of age and a smaller increase in females
• thin ventricular wall (MGI Ref ID J:102136)
  • males at 21 months of age, but not at 5.5 months, exhibit a decrease in left ventricular posterior wall
• decreased cardiac muscle contractility (MGI Ref ID J:102136)
  • males, but not females, exhibit a marked decrease in ejection fraction and shortening fraction at 21 months of age
• decreased vasodilation (MGI Ref ID J:103153)
  • insulin stimulation of muscle blood flow is about 40% smaller than in wild-type
• increased heart rate (MGI Ref ID J:102136)
  • heart rate is increased in males at 5.5 months of age but not at 21 months of age
  • heart rate is normal in females at 5.5 months of age but remains elevated at 21 months of age and does not fall with age as in wild-type
• homeostasis/metabolism phenotype
• abnormal blood chemistry (MGI Ref ID J:103153)
  • plasma nitrite and nitrate concentrations are about 60% lower than in wild-type, indicating a defect of vascular NO production
• hyperlipidemia (MGI Ref ID J:103153)
• increased circulating cholesterol level (MGI Ref ID J:103153)
  • insulin-resistant homozygotes have 50% higher plasma levels of cholesterol
• increased circulating free fatty acid level (MGI Ref ID J:103153)
  • insulin-resistant homozygotes have a 2-fold elevation of free fatty acid
• increased circulating insulin level (MGI Ref ID J:103153)
  • fasting plasma insulin concentration is elevated almost 2-fold
• increased circulating triglyceride level (MGI Ref ID J:103153)
  • insulin-resistant homozygotes have a 2-fold elevation of triglycerides
• abnormal glucose homeostasis (MGI Ref ID J:103153)
  • glucose infusion rate, glucose turnover rate, and glucose clearance rate are 30-40% lower during a hyperinsulinemic euglycemic clamp study
  • basal and insulin-stimulated glucose transport in isolated skeletal muscle is about 40% lower than in wild-type
• increased circulating insulin level (MGI Ref ID J:103153)
  • fasting plasma insulin concentration is elevated almost 2-fold
• insulin resistance (MGI Ref ID J:103153)
  • fasting hyperinsulinemia and glucose infusion rates during euglycemic clamp studies are 40% lower than in wild-type
• muscle phenotype
• decreased cardiac muscle contractility (MGI Ref ID J:102136)
  • males, but not females, exhibit a marked decrease in ejection fraction and shortening fraction at 21 months of age

Nos3^tm1Unc/Nos3^tm1Unc

        involves: 129P2/OlaHsd * C57BL/6J

• cardiovascular system phenotype
• abnormal vasodilation (MGI Ref ID J:54772)
  • aortic rings isolated from homozygous mutant mice show complete loss of endothelium-dependent vasorelaxation induced by acetylcholine and the calcium ionophore A23187
  • in contrast, vasorelaxations to the endothelium-independent vasodilator nitroglycerin are enhanced resulting in a shift of EC₅₀ by ~7-fold relative to wild-type values
• decreased heart rate (MGI Ref ID J:36559)
  • homozygotes display mild bradycardia relative to wild-type mice
  • notably, chronic treatment of homozygotes with L-NAME induces a significant decrease of heart rate in both wild-type mice and mutant mice
• increased blood pressure (MGI Ref ID J:36559)
  • increase in blood pressure by about 18 mmHg
• hypertension (MGI Ref ID J:54772)
  • homozygotes exhibit modest hypertension relative to wild-type mice
  • chronic treatment of homozygotes with NOS inhibitor L-NAME fails to further increase blood pressure; in contrast, chronic L-NAME treatment increases blood pressure in wild-type (C57BL/6J) mice to a level similar to that noted in mutant mice
• increased vasoconstriction (MGI Ref ID J:54772)
  • aortic rings isolated from homozygous mutant mice exhibit a significantly enhanced vasoconstriction in response to phenylephrine and a modestly enhanced vasoconstriction in response to serotonin
• growth/size phenotype
• decreased body weight (MGI Ref ID J:36559)
  • body weight is approximately 7.5% lower than wild-type at 14 weeks of age
• homeostasis/metabolism phenotype
• increased circulating renin level (MGI Ref ID J:36559)
  • plasma renin is nearly 2x that of wild-type

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Internal/Organ Research
Wound Healing (delayed/impaired)

Nos3^tm1Unc related

Cardiovascular Research
Heart Abnormalities (bradycardia)
Hypertension

Diabetes and Obesity Research
Insulin Resistance

Internal/Organ Research
Heart Abnormalities

Genes & Alleles

Gene & Allele Information

Allele Symbol		Nos3tm1Unc
Allele Name		targeted mutation 1, University of North Carolina
Allele Type		Targeted (knock-out)
Common Name(s)		NOS3-; eNOS-; ecNOS-;
Mutation Made By		Oliver Smithies,   University of North Carolina
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Nos3, nitric oxide synthase 3, endothelial cell
Chromosome		5
Gene Common Name(s)		2310065A03Rik; ECNOS; Nos-3; RIKEN cDNA 2310065A03 gene; eNOS; nitric oxide synthase 3 (indicible);
Molecular Note		A 1.2 kb neomycin cassette replaced 129 bp of exon 12 of the gene. This disrupted the calmodulin binding site of the protein and introduced a premature stop codon into the transcripts. Immunohistochemisty of heart and kidney sections from homozygous mutant mice confirmed that no detectable encoded protein was present. [MGI Ref ID J:36559]

Genotyping

Genotyping Information

Genotyping Protocols

Nos3^tm1Unc, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Shesely EG; Maeda N; Kim HS; Desai KM; Krege JH; Laubach VE; Sherman PA; Sessa WC; Smithies O. 1996. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 93(23):13176-81. [PubMed: 8917564]  [MGI Ref ID J:36559]

Additional References

Barouch LA; Harrison RW; Skaf MW; Rosas GO; Cappola TP; Kobeissi ZA; Hobai IA; Lemmon CA; Burnett AL; O'Rourke B; Rodriguez ER; Huang PL; Lima JA; Berkowitz DE; Hare JM. 2002. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416(6878):337-9. [PubMed: 11907582]  [MGI Ref ID J:75645]

Harada H; Pavlick KP; Hines IN; Lefer DJ; Hoffman JM; Bharwani S; Wolf RE; Grisham MB. 2003. Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: role of endothelial cell nitric oxide synthase. Proc Natl Acad Sci U S A 100(2):739-44. [PubMed: 12522262]  [MGI Ref ID J:81420]

Kaminski A; Pohl CB; Sponholz C; Ma N; Stamm C; Vollmar B; Steinhoff G. 2004. Up-regulation of endothelial nitric oxide synthase inhibits pulmonary leukocyte migration following lung ischemia-reperfusion in mice. Am J Pathol 164(6):2241-9. [PubMed: 15161656]  [MGI Ref ID J:91099]

Shankar RR; Wu Y; Shen HQ; Zhu JS; Baron AD. 2000. Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 49(5):684-7. [PubMed: 10905473]  [MGI Ref ID J:62229]

Tranguch S; Huet-Hudson Y. 2003. Decreased viability of nitric oxide synthase double knockout mice. Mol Reprod Dev 65(2):175-9. [PubMed: 12704728]  [MGI Ref ID J:83112]

de Jonge WJ; Hallemeesch MM; Kwikkers KL; Ruijter JM; de Gier-de Vries C; van Roon MA; Meijer AJ; Marescau B; de Deyn PP; Deutz NE; Lamers WH. 2002. Overexpression of arginase I in enterocytes of transgenic mice elicits a selective arginine deficiency and affects skin, muscle, and lymphoid development. Am J Clin Nutr 76(1):128-40. [PubMed: 12081826]  [MGI Ref ID J:80556]

Nos3^tm1Unc related

Adler S; Huang H; Loke KE; Xu X; Tada H; Laumas A; Hintze TH. 2001. Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO. Am J Physiol Renal Physiol 280(5):F838-43. [PubMed: 11292626]  [MGI Ref ID J:69293]

Akita Y; Otani H; Matsuhisa S; Kyoi S; Enoki C; Hattori R; Imamura H; Kamihata H; Kimura Y; Iwasaka T. 2007. Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS. Am J Physiol Heart Circ Physiol 292(5):H2051-9. [PubMed: 17259438]  [MGI Ref ID J:125942]

Arraj M; Lemmer B. 2006. Circadian rhythms in heart rate, motility, and body temperature of wild-type C57 and eNOS knock-out mice under light-dark, free-run, and after time zone transition. Chronobiol Int 23(4):795-812. [PubMed: 16887749]  [MGI Ref ID J:124720]

Balasubramaniam V; Maxey AM; Morgan DB; Markham NE; Abman SH. 2006. Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia. Am J Physiol Lung Cell Mol Physiol 291(1):L119-27. [PubMed: 16443642]  [MGI Ref ID J:121213]

Baumbach GL; Sigmund CD; Faraci FM. 2004. Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase. Circ Res 95(8):822-9. [PubMed: 15388643]  [MGI Ref ID J:102298]

Bearden SE. 2007. Advancing age produces sex differences in vasomotor kinetics during and after skeletal muscle contraction. Am J Physiol Regul Integr Comp Physiol 293(3):R1274-9. [PubMed: 17626125]  [MGI Ref ID J:124699]

Beierwaltes WH; Potter DL; Shesely EG. 2002. Renal baroreceptor-stimulated renin in the eNOS knockout mouse. Am J Physiol Renal Physiol 282(1):F59-64. [PubMed: 11739113]  [MGI Ref ID J:75596]

Bergula AP; Haidekker MA; Huang W; Stevens HY; Frangos JA. 2004. Venous ligation-mediated bone adaptation is NOS 3 dependent. Bone 34(3):562-9. [PubMed: 15003804]  [MGI Ref ID J:109405]

Borniquel S; Valle I; Cadenas S; Lamas S; Monsalve M. 2006. Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha. FASEB J 20(11):1889-91. [PubMed: 16891621]  [MGI Ref ID J:112736]

Bucci M; Roviezzo F; Posadas I; Yu J; Parente L; Sessa WC; Ignarro LJ; Cirino G. 2005. Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo. Proc Natl Acad Sci U S A 102(3):904-8. [PubMed: 15640348]  [MGI Ref ID J:96126]

Budzyn K; Marley PD; Sobey CG. 2004. Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice. Am J Physiol Regul Integr Comp Physiol 287(2):R342-8. [PubMed: 15130878]  [MGI Ref ID J:95774]

Buys ES; Raher MJ; Blake SL; Neilan TG; Graveline AR; Passeri JJ; Llano M; Perez-Sanz TM; Ichinose F; Janssens S; Zapol WM; Picard MH; Bloch KD; Scherrer-Crosbie M. 2007. Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload. Am J Physiol Heart Circ Physiol 293(1):H620-7. [PubMed: 17416602]  [MGI Ref ID J:126032]

Cabou C; Cani PD; Campistron G; Knauf C; Mathieu C; Sartori C; Amar J; Scherrer U; Burcelin R. 2007. Central insulin regulates heart rate and arterial blood flow: an endothelial nitric oxide synthase-dependent mechanism altered during diabetes. Diabetes 56(12):2872-7. [PubMed: 17804761]  [MGI Ref ID J:142487]

Cabrales P; Tsai AG; Frangos JA; Intaglietta M. 2005. Role of endothelial nitric oxide in microvascular oxygen delivery and consumption. Free Radic Biol Med 39(9):1229-37. [PubMed: 16214038]  [MGI Ref ID J:102115]

Calingasan NY; Huang PL; Chun HS; Fabian A; Gibson GE. 2000. Vascular factors are critical in selective neuronal loss in an animal model of impaired oxidative metabolism. J Neuropathol Exp Neurol 59(3):207-17. [PubMed: 10744059]  [MGI Ref ID J:62409]

Castrop H; Schweda F; Mizel D; Huang Y; Briggs J; Kurtz A; Schnermann J. 2004. Permissive role of nitric oxide in macula densa control of renin secretion. Am J Physiol Renal Physiol 286(5):F848-57. [PubMed: 15075180]  [MGI Ref ID J:113763]

Cauwels A; Janssen B; Buys E; Sips P; Brouckaert P. 2006. Anaphylactic shock depends on PI3K and eNOS-derived NO. J Clin Invest 116(8):2244-51. [PubMed: 16886062]  [MGI Ref ID J:113106]

Champion HC; Georgakopoulos D; Takimoto E; Isoda T; Wang Y; Kass DA. 2004. Modulation of in vivo cardiac function by myocyte-specific nitric oxide synthase-3. Circ Res 94(5):657-63. [PubMed: 14752030]  [MGI Ref ID J:97591]

Choi HC; Song P; Xie Z; Wu Y; Xu J; Zhang M; Dong Y; Wang S; Lau K; Zou MH. 2008. Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J Biol Chem 283(29):20186-97. [PubMed: 18474592]  [MGI Ref ID J:138750]

Connelly L; Madhani M; Hobbs AJ. 2005. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo. J Biol Chem 280(11):10040-6. [PubMed: 15647265]  [MGI Ref ID J:97766]

Cook S; Hugli O; Egli M; Menard B; Thalmann S; Sartori C; Perrin C; Nicod P; Thorens B; Vollenweider P; Scherrer U; Burcelin R. 2004. Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes 53(8):2067-72. [PubMed: 15277387]  [MGI Ref ID J:107196]

Deeb RS; Shen H; Gamss C; Gavrilova T; Summers BD; Kraemer R; Hao G; Gross SS; Laine M; Maeda N; Hajjar DP; Upmacis RK. 2006. Inducible nitric oxide synthase mediates prostaglandin h2 synthase nitration and suppresses eicosanoid production. Am J Pathol 168(1):349-62. [PubMed: 16400036]  [MGI Ref ID J:104432]

DiMagno MJ; Hao Y; Tsunoda Y; Williams JA; Owyang C. 2004. Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice. Am J Physiol Gastrointest Liver Physiol 286(3):G428-36. [PubMed: 14551061]  [MGI Ref ID J:95674]

Duplain H; Burcelin R; Sartori C; Cook S; Egli M; Lepori M; Vollenweider P; Pedrazzini T; Nicod P; Thorens B; Scherrer U. 2001. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104(3):342-5. [PubMed: 11457755]  [MGI Ref ID J:103153]

Elrod JW; Duranski MR; Langston W; Greer JJ; Tao L; Dugas TR; Kevil CG; Champion HC; Lefer DJ. 2006. eNOS gene therapy exacerbates hepatic ischemia-reperfusion injury in diabetes: a role for eNOS uncoupling. Circ Res 99(1):78-85. [PubMed: 16763164]  [MGI Ref ID J:123669]

Faraci FM; Sigmund CD; Shesely EG; Maeda N; Heistad DD. 1998. Responses of carotid artery in mice deficient in expression of the gene for endothelial NO synthase. Am J Physiol 274(2 Pt 2):H564-70. [PubMed: 9486260]  [MGI Ref ID J:45784]

Feng Q; Song W; Lu X; Hamilton JA; Lei M; Peng T; Yee SP. 2002. Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation 106(7):873-9. [PubMed: 12176963]  [MGI Ref ID J:103270]

Figueroa XF; Chen CC; Campbell KP; Damon DN; Day KH; Ramos S; Duling BR. 2007. Are voltage-dependent ion channels involved in the endothelial cell control of vasomotor tone? Am J Physiol Heart Circ Physiol 293(3):H1371-83. [PubMed: 17513486]  [MGI Ref ID J:126105]

Forbes MS; Thornhill BA; Park MH; Chevalier RL. 2007. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Am J Pathol 170(1):87-99. [PubMed: 17200185]  [MGI Ref ID J:117046]

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Sun D; Liu H; Yan C; Jacobson A; Ojaimi C; Huang A; Kaley G. 2006. COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice. Am J Physiol Heart Circ Physiol 291(3):H1429-35. [PubMed: 16632543]  [MGI Ref ID J:116431]

Sun J; Picht E; Ginsburg KS; Bers DM; Steenbergen C; Murphy E. 2006. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ Res 98(3):403-11. [PubMed: 16397145]  [MGI Ref ID J:118890]

Suzuki N; Motohashi N; Uezumi A; Fukada S; Yoshimura T; Itoyama Y; Aoki M; Miyagoe-Suzuki Y; Takeda S. 2007. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J Clin Invest 117(9):2468-76. [PubMed: 17786240]  [MGI Ref ID J:127415]

Tada H; Thompson CI; Recchia FA; Loke KE; Ochoa M; Smith CJ; Shesely EG; Kaley G; Hintze TH. 2000. Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart. Circ Res 86(3):270-4. [PubMed: 10679477]  [MGI Ref ID J:110253]

Takimoto E; Champion HC; Belardi D; Moslehi J; Mongillo M; Mergia E; Montrose DC; Isoda T; Aufiero K; Zaccolo M; Dostmann WR; Smith CJ; Kass DA. 2005. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 96(1):100-9. [PubMed: 15576651]  [MGI Ref ID J:104469]

Takimoto E; Champion HC; Li M; Ren S; Rodriguez ER; Tavazzi B; Lazzarino G; Paolocci N; Gabrielson KL; Wang Y; Kass DA. 2005. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 115(5):1221-1231. [PubMed: 15841206]  [MGI Ref ID J:98094]

Theodorakis NG; Wang YN; Skill NJ; Metz MA; Cahill PA; Redmond EM; Sitzmann JV. 2003. The role of nitric oxide synthase isoforms in extrahepatic portal hypertension: studies in gene-knockout mice. Gastroenterology 124(5):1500-8. [PubMed: 12730888]  [MGI Ref ID J:107756]

Thom SR; Bhopale VM; Velazquez OC; Goldstein LJ; Thom LH; Buerk DG. 2006. Stem cell mobilization by hyperbaric oxygen. Am J Physiol Heart Circ Physiol 290(4):H1378-86. [PubMed: 16299259]  [MGI Ref ID J:115770]

Tranguch S; Huet-Hudson Y. 2003. Decreased viability of nitric oxide synthase double knockout mice. Mol Reprod Dev 65(2):175-9. [PubMed: 12704728]  [MGI Ref ID J:83112]

Upmacis RK; Crabtree MJ; Deeb RS; Shen H; Lane PB; Benguigui LE; Maeda N; Hajjar DP; Gross SS. 2007. Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase. Am J Physiol Heart Circ Physiol 293(5):H2878-87. [PubMed: 17766468]  [MGI Ref ID J:132084]

Van Vliet BN; Chafe LL; Montani JP. 2003. Characteristics of 24 h telemetered blood pressure in eNOS-knockout and C57Bl/6J control mice. J Physiol 549(Pt 1):313-25. [PubMed: 12665600]  [MGI Ref ID J:105366]

Wang H; Kohr MJ; Wheeler DG; Ziolo MT. 2008. Endothelial nitric oxide synthase decreases {beta}-adrenergic responsiveness via inhibition of the L-type Ca2+ current. Am J Physiol Heart Circ Physiol 294(3):H1473-80. [PubMed: 18203845]  [MGI Ref ID J:132621]

Wang T. 2002. Role of iNOS and eNOS in modulating proximal tubule transport and acid-base balance. Am J Physiol Renal Physiol 283(4):F658-62. [PubMed: 12217856]  [MGI Ref ID J:113614]

Wang W; Mitra A; Poole B; Falk S; Lucia MS; Tayal S; Schrier R. 2004. Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure. Am J Physiol Renal Physiol 287(5):F1044-8. [PubMed: 15475535]  [MGI Ref ID J:95428]

Wang Y; Ahmad N; Kudo M; Ashraf M. 2004. Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning. Am J Physiol Heart Circ Physiol 287(3):H1125-31. [PubMed: 15142844]  [MGI Ref ID J:95593]

Xuan YT; Guo Y; Zhu Y; Wang OL; Rokosh G; Bolli R. 2007. Endothelial nitric oxide synthase plays an obligatory role in the late phase of ischemic preconditioning by activating the protein kinase C epsilon p44/42 mitogen-activated protein kinase pSer-signal transducers and activators of transcription1/3 pathway. Circulation 116(5):535-44. [PubMed: 17606840]  [MGI Ref ID J:139855]

Yamaguchi T; Kamada K; Dayton C; Gaskin FS; Yusof M; Yoshikawa T; Carter P; Korthuis RJ. 2007. Role of eNOS-derived NO in the postischemic anti-inflammatory effects of antecedent ethanol ingestion in murine small intestine. Am J Physiol Heart Circ Physiol 292(3):H1435-42. [PubMed: 17098834]  [MGI Ref ID J:120585]

Yang JZ; Ajonuma LC; Rowlands DK; Tsang LL; Ho LS; Lam SY; Chen WY; Zhou CX; Chung YW; Cho CY; Tse JY; James AE; Chan HC. 2005. The role of inducible nitric oxide synthase in gamete interaction and fertilization: a comparative study on knockout mice of three NOS isoforms. Cell Biol Int 29(9):785-91. [PubMed: 16087361]  [MGI Ref ID J:112824]

Yang XP; Liu YH; Shesely EG; Bulagannawar M; Liu F; Carretero OA. 1999. Endothelial nitric oxide gene knockout mice: cardiac phenotypes and the effect of angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension 34(1):24-30. [PubMed: 10406819]  [MGI Ref ID J:57364]

Yu J; deMuinck ED; Zhuang Z; Drinane M; Kauser K; Rubanyi GM; Qian HS; Murata T; Escalante B; Sessa WC. 2005. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci U S A 102(31):10999-1004. [PubMed: 16043715]  [MGI Ref ID J:100484]

Zhang YH; Zhang MH; Sears CE; Emanuel K; Redwood C; El-Armouche A; Kranias EG; Casadei B. 2008. Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice. Circ Res 102(2):242-9. [PubMed: 18007024]  [MGI Ref ID J:141557]

Zhao HJ; Wang S; Cheng H; Zhang MZ; Takahashi T; Fogo AB; Breyer MD; Harris RC. 2006. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17(10):2664-9. [PubMed: 16971655]  [MGI Ref ID J:135864]

Zhao X; Chen YR; He G; Zhang A; Druhan LJ; Strauch AR; Zweier JL. 2007. Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart. Am J Physiol Heart Circ Physiol 292(3):H1541-50. [PubMed: 17114245]  [MGI Ref ID J:120584]

Zhao X; He G; Chen YR; Pandian RP; Kuppusamy P; Zweier JL. 2005. Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport. Circulation 111(22):2966-72. [PubMed: 15939832]  [MGI Ref ID J:112252]

Zhao X; Lu X; Feng Q. 2002. Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis. Am J Physiol Heart Circ Physiol 283(6):H2371-8. [PubMed: 12388304]  [MGI Ref ID J:108272]

Zhou Y; Mitra S; Varadharaj S; Parinandi N; Zweier JL; Flavahan NA. 2006. Increased expression of cyclooxygenase-2 mediates enhanced contraction to endothelin ETA receptor stimulation in endothelial nitric oxide synthase knockout mice. Circ Res 98(11):1439-45. [PubMed: 16645140]  [MGI Ref ID J:122612]

Zhou Y; Varadharaj S; Zhao X; Parinandi N; Flavahan NA; Zweier JL. 2005. Acetylcholine causes endothelium-dependent contraction of mouse arteries. Am J Physiol Heart Circ Physiol 289(3):H1027-32. [PubMed: 15879486]  [MGI Ref ID J:115427]

Zhu X; Liu B; Zhou S; Chen YR; Deng Y; Zweier JL; He G. 2007. Ischemic preconditioning prevents in vivo hyperoxygenation in postischemic myocardium with preservation of mitochondrial oxygen consumption. Am J Physiol Heart Circ Physiol 293(3):H1442-50. [PubMed: 17513495]  [MGI Ref ID J:126163]

Zuckerbraun BS; Chin BY; Wegiel B; Billiar TR; Czsimadia E; Rao J; Shimoda L; Ifedigbo E; Kanno S; Otterbein LE. 2006. Carbon monoxide reverses established pulmonary hypertension. J Exp Med 203(9):2109-19. [PubMed: 16908624]  [MGI Ref ID J:124569]

de Jonge WJ; Hallemeesch MM; Kwikkers KL; Ruijter JM; de Gier-de Vries C; van Roon MA; Meijer AJ; Marescau B; de Deyn PP; Deutz NE; Lamers WH. 2002. Overexpression of arginase I in enterocytes of transgenic mice elicits a selective arginine deficiency and affects skin, muscle, and lymphoid development. Am J Clin Nutr 76(1):128-40. [PubMed: 12081826]  [MGI Ref ID J:80556]

de Jonge WJ; Kwikkers KL; te Velde AA; van Deventer SJ; Nolte MA; Mebius RE; Ruijter JM; Lamers MC; Lamers WH. 2002. Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice. J Clin Invest 110(10):1539-48. [PubMed: 12438451]  [MGI Ref ID J:80204]

van Der Heyde HC; Gu Y; Zhang Q; Sun G; Grisham MB. 2000. Nitric oxide is neither necessary nor sufficient for resolution of plasmodium chabaudi malaria in mice J Immunol 165(6):3317-23. [PubMed: 10975849]  [MGI Ref ID J:64564]

van der Heijden OW; Essers YP; Fazzi G; Peeters LL; De Mey JG; van Eys GJ. 2005. Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice. Biol Reprod 72(5):1161-8. [PubMed: 15659709]  [MGI Ref ID J:104639]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX1

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes (by homozygous sibling matings).
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply	Level 2. Up to 100 mice. Larger quantities or custom orders arranged upon request.
Supply Notes	Shipped at a specific age in weeks. Mice at a precise age in days, littermates and retired breeders are also available. Strains that must be genotyped are not available until five to seven weeks of age. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.