JAX Mouse Strain Datasheet - 008286

129S6.129P2(B6)-Nos3^tm1Unc/J

Stock No:: 008286 |; 129S6-Nos3

Cryo Recovery

Overview

Also Known As: 129S6-Nos3

129S6/SvEvTac mice homozygous for this Nos3 (nitric oxide synthase 3, endothelial cell) targeted mutation, Nos3^tm1Unc, provide another genetic background that may be useful for studying wound healing, hypertension and other cardiovascular defects, insulin resistance, hyperlipidemia and lung development.

Donating Investigator

Dr. Oliver Smithies, University of North Carolina

Genetic overview

Genetic Background	Generation
129S6/SvEvTac

Nos3^tm1Unc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nos3	nitric oxide synthase 3, endothelial cell

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Research Applications

Cardiovascular Research
Diabetes and Obesity Research
Internal/Organ Research
Metabolism Research

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Base Price

Starting at:

$2,625.00 Domestic price Cryo Recovery

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Details

Detailed Description

Homozygous mutant mice 129S6/SvEvTac background are viable, fertile, normal in size and do not exhibit any gross physical or behavioral abnormalities.

On the C57BL/6 congenic background homozygous mutants mice exhibit 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. This mutant mouse strain may be useful in studies of wound healing, hypertension and other cardiovascular defects, insulin resistance, hyperlipidemia and lung development.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to replace 129bp exon 12, which disrupted the calmodulin binding domain. The construct was electroporated into 129P2OlaHsd derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting male chimeric animals were crossed to C57BL/6 female mice. Heterozygotes were intercrossed to generate homozygotes. The mice were subsequently backcrossed on to the C57BL/6J background for 12 generations. The mice were then backcrossed to 129S6/SvEvTac for at least 10 generations prior to intercrossing. In 2008, The Jackson Laboratory backcrossed this stock to 129S6/SvEvTac for one generation prior to intercrossing to generate homozygotes. Additional SNP's testing indicates 104 markers tested spanning all chromosomes are 129S6 in origin.

Control Suggestions

Approximate Controls

None Available

Additional Information

Considerations for Choosing Controls

Selected References

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: J:36559

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Genetics

Nos3^tm1Unc

Allele Symbol: Nos3^tm1Unc

Allele Name	targeted mutation 1, University of North Carolina
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	NOS3-; eNOS-; eNOSKO; ecNOS-
Gene Symbol and Name	Nos3, nitric oxide synthase 3, endothelial cell
Gene Synonym(s)	2310065A03Rik; 2310065A03Rik; ECNOS; Nos-3; Nos-3; RIKEN cDNA 2310065A03 gene; eNOS; eNos; ecNOS; nitric oxide synthase 3 (indicible)
Strain of Origin	129P2/OlaHsd
Chromosome	5
General Note	Phenotypic Similarity to Human Syndrome: Aortic Valve Disease in Homozygous mice (J:103340)
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.
Mutations Made By	Dr. Oliver Smithies, University of North Carolina

Disease/Phenotype

Disease Terms

Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.

Research Areas By Genotype

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

Cardiovascular Research
- Atherosclerosis
- Hypertension
Diabetes and Obesity Research
- Insulin Resistance
Internal/Organ Research
- Wound Healing
Metabolism Research
- Lipid Metabolism

Genotype: Nos3^tm1Unc related

Cardiovascular Research
- Heart Abnormalities
  - bradycardia
- Hypertension
Diabetes and Obesity Research
- Insulin Resistance
Internal/Organ Research
- Heart Abnormalities

Mammalian Phenotype Terms by Genotype

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd

mortality/aging

premature death
- 50% of males die by 21 months of age, however female survival is similar to wild-type

growth/size/body region phenotype

decreased body weight
- both males and females weight less than wild-type at 21 months of age

cardiovascular system phenotype

abnormal heart morphology
- at 21 months of age, males exhibit wall thinning of the heart while females display an increase in wall thickness of the heart

abnormal interventricular septum morphology
- 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

abnormal systemic arterial blood pressure

cardiac hypertrophy
- at 21 months of age, males have a large increase and females have a slight increase in heart size

decreased cardiac muscle contractility
- males, but not females, exhibit a marked decrease in ejection fraction and shortening fraction at 21 months of age

decreased vasodilation
- insulin stimulation of muscle blood flow is about 40% smaller than in wild-type

dilated heart left ventricle
- left ventricular mass (LVMASS) is increased in both males and females at 21 months of age
- 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
- ratio between LVMASS and LV volume is increased in 21 month old males

hypertension
- 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 heart rate
- 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

increased heart weight
- 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

increased systemic arterial blood pressure
- at 21 months of age, females, but not males, continue to exhibit increased mean blood pressure
- mean blood pressure is significantly elevated in both males and females at 5.5 months of age

increased systemic arterial diastolic blood pressure
- at 21 months of age, females, but not males, continue to exhibit an increased diastolic blood pressure
- elevated at 5.5 months of age in both males and females

increased systemic arterial systolic blood pressure
- at 21 months of age, females, but not males, continue to exhibit an increased systolic blood pressure
- elevated at 5.5 months of age in both males and females

thin ventricular wall
- males at 21 months of age, but not at 5.5 months, exhibit a decrease in left ventricular posterior wall

homeostasis/metabolism phenotype

abnormal blood homeostasis
- plasma nitrite and nitrate concentrations are about 60% lower than in wild-type, indicating a defect of vascular NO production

abnormal glucose homeostasis
- basal and insulin-stimulated glucose transport in isolated skeletal muscle is about 40% lower than in wild-type
- glucose infusion rate, glucose turnover rate, and glucose clearance rate are 30-40% lower during a hyperinsulinemic euglycemic clamp study

hyperlipidemia

increased circulating cholesterol level
- insulin-resistant homozygotes have 50% higher plasma levels of cholesterol

increased circulating free fatty acid level
- insulin-resistant homozygotes have a 2-fold elevation of free fatty acid

increased circulating insulin level
- fasting plasma insulin concentration is elevated almost 2-fold

increased circulating triglyceride level
- insulin-resistant homozygotes have a 2-fold elevation of triglycerides

insulin resistance
- fasting hyperinsulinemia and glucose infusion rates during euglycemic clamp studies are 40% lower than in wild-type

muscle phenotype

decreased cardiac muscle contractility
- males, but not females, exhibit a marked decrease in ejection fraction and shortening fraction at 21 months of age

decreased vasodilation
- insulin stimulation of muscle blood flow is about 40% smaller than in wild-type

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Nos3^tm1Unc/Nos3⁺
involves: 129P2/OlaHsd * C57BL/6J

cardiovascular system phenotype

increased vasodilation
- 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

muscle phenotype

increased vasodilation
- 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

Genotype: Nos3^tm1Unc/Nos3⁺
B6.129P2-Nos3^tm1Unc/J

mortality/aging

postnatal lethality, incomplete penetrance
- 38% of mice die by P10 compared with 13% of wild-type mice

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
B6.129P2-Nos3^tm1Unc

cardiovascular system phenotype

abnormal blood-brain barrier function
- kainic acid injection of hippocampi does not cause blood-brain barrier breakdown

nervous system phenotype

abnormal blood-brain barrier function
- kainic acid injection of hippocampi does not cause blood-brain barrier breakdown

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd * C57BL/6J

cardiovascular system phenotype

abnormal vasodilation
- 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
- 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

hypertension
- 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
- homozygotes exhibit modest hypertension relative to wild-type mice

increased systemic arterial blood pressure
- increase in blood pressure by about 18 mmHg

increased vasoconstriction
- 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/body region phenotype

decreased body weight
- body weight is approximately 7.5% lower than wild-type at 14 weeks of age

homeostasis/metabolism phenotype

homeostasis/metabolism phenotype
- unlike mice null for Nos1 or Nos2, no abnormalities in urine pH or bicarbonate concentrations are detected

increased circulating renin level
- plasma renin is nearly 2x that of wild-type

muscle phenotype

abnormal vasodilation
- 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

increased vasoconstriction
- 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

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
BKS.129P2-Nos3^tm1Unc

renal/urinary system phenotype

albuminuria
- moderate albuminuria is observed at 26 weeks of age

homeostasis/metabolism phenotype

albuminuria
- moderate albuminuria is observed at 26 weeks of age

cardiovascular system phenotype

increased systemic arterial systolic blood pressure
- observed by 24 to 28 weeks of age

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd * C57BL/6

mortality/aging

decreased sensitivity to induced morbidity/mortality
- after injection of platelet-activating factor (PAF), less than 10% mortality occurs within 30 minutes
- 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
- 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

growth/size/body region phenotype

decreased body weight
- body weight is signifcantly lower than controls at 14 days of age
- body weights at 14 weeks of age are approximately 7.5% lower than in wild-type

homeostasis/metabolism phenotype

decreased body temperature
- 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
- plasma renin concentrations are nearly twice as high as in wild-type

cardiovascular system phenotype

abnormal cardiovascular system morphology

abnormal cardiovascular system physiology

abnormal heart right ventricle pressure
- mean right ventricular pressure is elevated in males but not in females

abnormal heart weight
- right ventricle/body weight ratio increased in males
- right ventricle/left ventricle+septum ratio increased in males

abnormal pulmonary artery morphology
- larger than in controls but only at 14 day
- medial wall area is greater than in controls in the fetus
- muscularity decreases after birth
- muscularity in females is like controls by 14 days of age
- muscularity is reduced in the male but still greater than controls

decreased heart rate
- 670 beats per min vs. 709 beats per min in wild-type

decreased vascular permeability
- 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 mean systemic arterial blood pressure
- elevated in males but not in females

increased systemic arterial blood pressure

immune system phenotype

immune system phenotype
- exhibit a similar susceptibility to lipopolysaccharide-induced death as wild type
- exhibit a similar susceptibility to lipopolysaccharide-induced death as wild-type

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
B6.129P2-Nos3^tm1Unc/J

mortality/aging

neonatal lethality, incomplete penetrance
- about 40% die within the first hour of birth

postnatal lethality, incomplete penetrance
- 85% of mice die by P10 compared with 13% of wild-type mice

immune system phenotype

abnormal osteoclast physiology
- serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points

increased inflammatory response
- fever in response to turpentine injection is enhanced compared to wild-type controls
- unlike in mice null for either Nos1 or Nos2, fever in response to LPS injection is not significantly different from wild-type controls

kidney inflammation
- after remnant kidney surgery, homozygotes exhibit increased macrophage infiltration in the glomeruli (15.4-fold) and in the tubulointerstitium (2.7-fold) relative to similarly-treated wild-type controls
- however, a similar increase in glomerular T-cell infiltration (62%) is seen in both RK groups

renal/urinary system phenotype

abnormal glomerular capillary endothelium morphology
- after remnant kidney surgery, homozygotes exhibit a significantly greater endothelial cell loss than similarly-treated wild-type controls

abnormal kidney cortex morphology
- after remnant kidney surgery, homozygotes exhibit a 44% increase in tubulointerstitial injury relative to similarly-treated wild-type controls

abnormal kidney morphology
- 4% of glomeruli outside scarred area exhibit loss of cellularity and vasculature, a hyalinization like appearance
- in 80% of adult freshly isolated kidneys indentations are observed, indicating zones of parenchymal scarring

abnormal proximal convoluted tubule morphology
- the glomeruli often display no clear connection to typical large-diameter proximal tubules

abnormal renal glomerulus morphology
- glomeruli within scarred areas are considerably smaller than wild-type

abnormal renal tubule epithelium morphology
- after remnant kidney surgery, homozygotes exhibit more severe sloughing , vacuolization and nuclear exfoliation of tubular epithelial cells relative to similarly-treated wild-type controls

albuminuria
- after remnant kidney surgery, homozygotes exhibit a significantly higher increase in urinary albumin excretion relative to similarly-treated wild-type controls

decreased kidney cell proliferation
- after remnant kidney surgery, homozygotes exhibit a 36% reduction of proliferating endothelial cells in cortical peritubular capillaries relative to similarly-treated wild-type controls

dilated renal glomerular capsule

dilated renal tubules
- after remnant kidney surgery, homozygotes exhibit more severe tubular dilatation than similarly-treated wild-type controls

expanded mesangial matrix
- after remnant kidney surgery, homozygotes exhibit increased matrix deposition in some glomeruli unlike similarly-treated wild-type controls

glomerular capillary thrombosis
- after remnant kidney surgery, homozygotes develop intraluminal thrombi unlike similarly-treated wild-type controls

glomerulosclerosis
- after remnant kidney surgery, homozygotes develop significant glomerulosclerosis, unlike similarly-treated wild-type controls
- within scarred areas

increased kidney apoptosis
- at 2 months after right subcapsular nephrectomy and surgical resection of the poles of the left kidney to produce a remnant kidney (RK) model, homozygotes exhibit a 4.6-fold increase in peritubular endothelial cell apoptosis relative to similarly-treated wild-type controlswild-type controls

increased renal tubule apoptosis
- in two week old mice based upon TUNEL staining and the presence of Apoptotic nuclei with a dense punctate appearance

kidney degeneration
- degeneration of the glomerular core components is common within the scarred zones

kidney failure
- after remnant kidney surgery, homozygotes exhibit significantly worse renal function relative to similarly-treated wild-type controls

kidney inflammation
- after remnant kidney surgery, homozygotes exhibit increased macrophage infiltration in the glomeruli (15.4-fold) and in the tubulointerstitium (2.7-fold) relative to similarly-treated wild-type controls
- however, a similar increase in glomerular T-cell infiltration (62%) is seen in both RK groups

kidney microaneurysm
- after remnant kidney surgery, homozygotes develop microaneurysms unlike similarly-treated wild-type controls

mesangial cell hyperplasia
- after remnant kidney surgery, homozygotes exhibit increased mesangial proliferation relative to similarly-treated wild-type controls

mesangiolysis
- after remnant kidney surgery, homozygotes develop mesangiolysis unlike similarly-treated wild-type controls

renal cast
- after remnant kidney surgery, homozygotes exhibit more severe tubular cast formation than similarly-treated wild-type controls

renal glomerulus fibrosis
- after remnant kidney surgery, homozygotes exhibit a 46% increase in glomerular collagen IV deposition relative to similarly-treated wild-type controls

renal glomerulus hypertrophy
- after remnant kidney surgery, homozygotes develop significantly greater glomerular hypertrophy than similarly-treated wild-type controls

renal glomerulus lipidosis
- frequently a large lipid droplet is observed with Bowman's capsule and the adjacent matrix

renal hypoplasia
- within scarred areas

renal interstitial fibrosis
- after remnant kidney surgery, homozygotes exhibit a 38% increase in collagen III deposition in the tubulointerstitium relative to similarly-treated wild-type controls
- thin strands of connective tissue distributed loosely within the interglomerular interstitium

renal tubular necrosis
- in 2 week old mice, as pyknotic nuclei and vacuolated cytoplasm are observed

skeleton phenotype

abnormal osteoblast physiology
- serum osteocalcin (BGLAP) levels are significantly higher in sham compared wit wild-type sham mice at baseline and at 14 wk and remained higher

abnormal osteoclast physiology
- serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points

decreased bone mineral density
- exagerated BMD decrease in ovariectomized mice

increased bone mineral density
- between 10-20 weeks post sham-operation compared to sham-operated wild-type

increased compact bone thickness
- significantly greater cortical thickness in sham operated mice compared to sham operated wild-type mice

hematopoietic system phenotype

abnormal osteoclast physiology
- serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points

growth/size/body region phenotype

fetal growth retardation
- Intrauterine Growth Retardation demonstrated by ultrasonographic imaging showing differences in embryo and gestational vesicle measurements in both longitudinal and transversal curves from Days 5.5 to 14.5.
- fetuses from E18 to term demonstrate slight growth retardation

cardiovascular system phenotype

abnormal angiogenesis
- 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 glomerular capillary endothelium morphology
- after remnant kidney surgery, homozygotes exhibit a significantly greater endothelial cell loss than similarly-treated wild-type controls

abnormal heart morphology
- diastolic dimension is increased compared to in wild-type mice

abnormal interventricular septum membranous part morphology

abnormal lung vasculature morphology
- abnormalities in pulmonary vascular development
- capillaries of preterm mice remain deep within thickened septae, instead of aligning with the saccular epithelium, resulting in significantly fewer capillaries abutting saccular airspaces
- disorganization of the extracellular matrix structure in the lung vasculature

abnormal systemic arterial blood pressure
- at 2 months after right subcapsular nephrectomy and surgical resection of the poles of the left kidney to produce a remnant kidney (RK) model, homozygotes fail to exhibit a further increase in systolic blood pressure relative to sham-operated homozygotes, unlike wild-type controls unlike wild-type controls

abnormal vascular branching morphogenesis
- E19.5 lungs show dramatic decrease of arteriolar branches and regions of marked capillary hypoperfusion

bicuspid aortic valve
- high incidence (5 of 12) bicuspid aortic valves, however do not exhibit aortic coarctation

cardiac hypertrophy
- 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
- however, homozygotes show no significant differences in baseline heart weight or myocyte size relative to wild-type mice
- 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 progressioneeks, with minimal further progression

decreased cardiac muscle contractility

decreased vascular endothelial cell number
- after remnant kidney surgery, homozygotes exhibit a significantly greater decrease (50%) in endothelial cell density in the glomeruli and renal cortex relative to similarly-treated wild-type controls

enlarged heart

enlarged heart atrium

glomerular capillary thrombosis
- after remnant kidney surgery, homozygotes develop intraluminal thrombi unlike similarly-treated wild-type controls

increased fetal cardiomyocyte apoptosis
- at E12.5, E15.5 and P1 in the myocardium
- in fetal atrioventricular endothelial cushions, septum primum and right and left ventricular myocardium

increased heart left ventricle size

increased heart right ventricle size

increased heart ventricle size
- ventricular hypertrophy

increased left ventricle systolic pressure
- 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
- 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 functionstolic chamber volumes, as well as preserved wall thickness and fractional shortening, indicating preserved or enhanced systolic and diastolic function

kidney microaneurysm
- after remnant kidney surgery, homozygotes develop microaneurysms unlike similarly-treated wild-type controls

lung hemorrhage
- E16 lungs show scattered areas of parenchymal and interlobar hemorrhages

muscular ventricular septal defect

ostium secundum atrial septal defect

pulmonary vascular congestion
- severe with focal alveolar edema

ventricular septal defect
- membranous and muscular ventricular defects in 6 of 10 mice compared with 1 of 10 atrial septal defects in wild-type mice

respiratory system phenotype

abnormal lung morphology
- E16 lungs display scattered subpleural hematomas
- E20 lungs display absence of discernible basement membrane in the distal airways
- exhibit a decrease in apoptosis in the lungs
- fetal lungs demonstrate abnormally compact lung structure and lungs of pups show evidence of septal thickening and reduced airspaces

abnormal lung vasculature morphology
- abnormalities in pulmonary vascular development
- capillaries of preterm mice remain deep within thickened septae, instead of aligning with the saccular epithelium, resulting in significantly fewer capillaries abutting saccular airspaces
- disorganization of the extracellular matrix structure in the lung vasculature

abnormal surfactant secretion
- lack of surfactant in bronchial alveolar lavage fluid

abnormal type II pneumocyte morphology
- observe an increase in markedly swollen glycogen laden pneumocytes protruding into airspaces compared to wild-type

absent alveolar lamellar bodies
- no evidence of lamellar bodies in type II pneumocytes

lung hemorrhage
- E16 lungs show scattered areas of parenchymal and interlobar hemorrhages

pulmonary alveolar edema

pulmonary vascular congestion
- severe with focal alveolar edema

respiratory distress
- some newborns exhibit severe respiratory distress

thick pulmonary interalveolar septum
- pups exhibit marked septal thickening

homeostasis/metabolism phenotype

abnormal circulating protein level
- serum TRAP5b (ACP5) concentrations are significantly higher in sham treated compared wild-type sham treated mice at all time points
- serum osteocalcin (BGLAP) levels are significantly higher in sham treated compared to wild-type sham mice at baseline, 14 weeks and remained higher

albuminuria
- after remnant kidney surgery, homozygotes exhibit a significantly higher increase in urinary albumin excretion relative to similarly-treated wild-type controls

cyanosis
- some newborns show varying levels of cyanosis

glomerular capillary thrombosis
- after remnant kidney surgery, homozygotes develop intraluminal thrombi unlike similarly-treated wild-type controls

increased blood urea nitrogen level
- after remnant kidney surgery, homozygotes exhibit a significantly higher increase in BUN levels relative to similarly-treated wild-type controls

increased circulating creatine kinase level
- after remnant kidney surgery, homozygotes exhibit a significantly higher increase in serum creatinine levels relative to similarly-treated wild-type controls

pulmonary alveolar edema

muscle phenotype

decreased cardiac muscle contractility

increased ventricle muscle contractility
- 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 functionstolic chamber volumes, as well as preserved wall thickness and fractional shortening, indicating preserved or enhanced systolic and diastolic function

cellular phenotype

abnormal redox activity
- 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

decreased kidney cell proliferation
- after remnant kidney surgery, homozygotes exhibit a 36% reduction of proliferating endothelial cells in cortical peritubular capillaries relative to similarly-treated wild-type controls

increased fetal cardiomyocyte apoptosis
- at E12.5, E15.5 and P1 in the myocardium
- in fetal atrioventricular endothelial cushions, septum primum and right and left ventricular myocardium

increased kidney apoptosis
- at 2 months after right subcapsular nephrectomy and surgical resection of the poles of the left kidney to produce a remnant kidney (RK) model, homozygotes exhibit a 4.6-fold increase in peritubular endothelial cell apoptosis relative to similarly-treated wild-type controlswild-type controls

increased renal tubule apoptosis
- in two week old mice based upon TUNEL staining and the presence of Apoptotic nuclei with a dense punctate appearance

endocrine/exocrine gland phenotype

abnormal ovary morphology
- on day 0.5 of estrous cycle, mutant ovaries display a scarce number of ovulation sites and a higher number of anovulatory and luteinized unruptured follicles relative to wild-type controls

decreased corpora lutea number
- on day 0.5 of estrous cycle, mutant ovaries exhibit significantly less corpora lutea than wild-type ovaries (9.7 +/- 1.2 versus 14.2 +/- 1.2, respectively)

small ovary
- on day 0.5 of estrous cycle, mutant ovaries are significantly smaller than wild-type

reproductive system phenotype

abnormal ovary morphology
- on day 0.5 of estrous cycle, mutant ovaries display a scarce number of ovulation sites and a higher number of anovulatory and luteinized unruptured follicles relative to wild-type controls

abnormal pregnancy
- in mutant dams, the highest %s of embryo losses occur between days 8.5 and 10.5 (55.6%) and at day 13.5 postcoitum (44.4% of total losses), whereas in control dams embryo losses occur at days 10.5 and 11.5 postcoitum
- mutant dams show a higher incidence of embryo losses than wild-type dams (62.5% versus 16.7%, respectively)
- the mean rate of embryo losses detected in mutant dams is 49.90.1% versus less than 20% in wild-type dams

anovulation
- female homozygotes display a higher rate of anovulation than wild-type controls (48.3 +/- 7.3% versus 29.7 +/- 6.3, respectively)

decreased corpora lutea number
- on day 0.5 of estrous cycle, mutant ovaries exhibit significantly less corpora lutea than wild-type ovaries (9.7 +/- 1.2 versus 14.2 +/- 1.2, respectively)

decreased fertilization frequency
- on day 0.5 of estrous cycle, female homozygotes show a significant reduction in the total number of recovered embryos (oocytes/zygotes) relative to wild-type controls (4.0 +/- 1.1 versus 10.4 +/- 1.6, respectively)
- thereafter, a mean of 2.0 +/- 1.0 of these recovered embryos are found to be fertilized, representing a non-fertilization rate of 50.7% versus only 3.3% in control littermates

decreased ovulation rate
- female homozygotes display a lower ovulation rate than wild-type controls (9.7 +/- 1.2% versus 14.2 +/- 1.2%, respectively)

impaired embryo implantation
- on days 6.5 and 8.5 of pregnancy, the average number of embryos reaching implantation is lower in mutant mice relative to wild-type mice (4.0 +/- 0.4 versus 7.5 +/- 0.4, respectively)

small ovary
- on day 0.5 of estrous cycle, mutant ovaries are significantly smaller than wild-type

References

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Additional - Nos3^tm1Unc related

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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: J:95593
Wegiel B; Gallo D; Csizmadia E; Roger T; Kaczmarek E; Harris C; Zuckerbraun BS; Otterbein LE. 2011. Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase. Proc Natl Acad Sci U S A 108(46):18849-54. PubMed: 22042868 MGI: J:180223
Whiteus C; Freitas C; Grutzendler J. 2014. Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature 505(7483):407-11. PubMed: 24305053 MGI: J:207919
Whiting C; Castillo A; Haque MZ; Majid DS. 2013. Protective role of the endothelial isoform of nitric oxide synthase in ANG II-induced inflammatory responses in the kidney. Am J Physiol Renal Physiol 305(7):F1031-41. PubMed: 23926180 MGI: J:202044
Wu M; Tsirka SE. 2009. Endothelial NOS-deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis. Glia 57(11):1204-15. PubMed: 19170181 MGI: J:156206
Xing J; Liu H; Yang H; Chen R; Chen Y; Xu J. 2014. Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy. PLoS One 9(12):e116165. PubMed: 25541949 MGI: J:225384
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: J:139855
Yagi S; Aihara K; Ikeda Y; Sumitomo Y; Yoshida S; Ise T; Iwase T; Ishikawa K; Azuma H; Akaike M; Matsumoto T. 2008. Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency. Circ Res 102(1):68-76. PubMed: 17967781 MGI: J:145596
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: 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: 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: J:57364
Yang Z; Chiou TT; Stossel TP; Kobzik L. 2015. Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function. Am J Physiol Lung Cell Mol Physiol 309(1):L11-6. PubMed: 25957291 MGI: J:232448
Yang Z; Huang YC; Koziel H; de Crom R; Ruetten H; Wohlfart P; Thomsen RW; Kahlert JA; Sorensen HT; Jozefowski S; Colby A; Kobzik L. 2014. Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target. Elife 3:. PubMed: 25317947 MGI: J:218028
Yang Z; Wang ZE; Doulias PT; Wei W; Ischiropoulos H; Locksley RM; Liu L. 2010. Lymphocyte Development Requires S-nitrosoglutathione Reductase. J Immunol 185(11):6664-9. PubMed: 20980633 MGI: J:166150
Yazji I; Sodhi CP; Lee EK; Good M; Egan CE; Afrazi A; Neal MD; Jia H; Lin J; Ma C; Branca MF; Prindle T; Richardson WM; Ozolek J; Billiar TR; Binion DG; Gladwin MT; Hackam DJ. 2013. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc Natl Acad Sci U S A 110(23):9451-6. PubMed: 23650378 MGI: J:197450
Ye H; Charpin-El Hamri G; Zwicky K; Christen M; Folcher M; Fussenegger M. 2013. Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome. Proc Natl Acad Sci U S A 110(1):141-6. PubMed: 23248313 MGI: J:192622
Yokoyama M; Okada S; Nakagomi A; Moriya J; Shimizu I; Nojima A; Yoshida Y; Ichimiya H; Kamimura N; Kobayashi Y; Ohta S; Fruttiger M; Lozano G; Minamino T. 2014. Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. Cell Rep 7(5):1691-703. PubMed: 24857662 MGI: J:211787
Yu J; Zhang Y; Zhang X; Rudic RD; Bauer PM; Altieri DC; Sessa WC. 2012. Endothelium derived nitric oxide synthase negatively regulates the PDGF-survivin pathway during flow-dependent vascular remodeling. PLoS One 7(2):e31495. PubMed: 22355372 MGI: J:185226
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: J:100484
Yusof M; Kamada K; Kalogeris T; Gaskin FS; Korthuis RJ. 2009. Hydrogen sulfide triggers late-phase preconditioning in postischemic small intestine by an NO- and p38 MAPK-dependent mechanism. Am J Physiol Heart Circ Physiol 296(3):H868-76. PubMed: 19168723 MGI: J:146878
Zhang M; Takimoto E; Lee DI; Santos CX; Nakamura T; Hsu S; Jiang A; Nagayama T; Bedja D; Yuan Y; Eaton P; Shah AM; Kass DA. 2012. Pathological cardiac hypertrophy alters intracellular targeting of phosphodiesterase type 5 from nitric oxide synthase-3 to natriuretic peptide signaling. Circulation 126(8):942-51. PubMed: 22829024 MGI: J:202198
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: 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: 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: 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: 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: J:108272
Zhao YY; Zhao YD; Mirza MK; Huang JH; Potula HH; Vogel SM; Brovkovych V; Yuan JX; Wharton J; Malik AB. 2009. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 119(7):2009-18. PubMed: 19487814 MGI: J:152579
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: J:122612
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Also Known As: 129S6-Nos3

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Nos3tm1Unc

Allele Symbol: Nos3tm1Unc

Disease Terms

Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.

Research Areas By Genotype

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

Genotype: Nos3tm1Unc related

Mammalian Phenotype Terms by Genotype

Genotype: Nos3tm1Unc/Nos3tm1Uncinvolves: 129P2/OlaHsd

mortality/aging

growth/size/body region phenotype

cardiovascular system phenotype

homeostasis/metabolism phenotype

muscle phenotype

Genotype: Nos3tm1Unc/Nos3+involves: 129P2/OlaHsd * C57BL/6J

cardiovascular system phenotype

muscle phenotype

Genotype: Nos3tm1Unc/Nos3+B6.129P2-Nos3tm1Unc/J

mortality/aging

Genotype: Nos3tm1Unc/Nos3tm1UncB6.129P2-Nos3tm1Unc

cardiovascular system phenotype

nervous system phenotype

Genotype: Nos3tm1Unc/Nos3tm1Uncinvolves: 129P2/OlaHsd * C57BL/6J

cardiovascular system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

muscle phenotype

Genotype: Nos3tm1Unc/Nos3tm1UncBKS.129P2-Nos3tm1Unc

renal/urinary system phenotype

homeostasis/metabolism phenotype

cardiovascular system phenotype

Genotype: Nos3tm1Unc/Nos3tm1Uncinvolves: 129P2/OlaHsd * C57BL/6

mortality/aging

growth/size/body region phenotype

homeostasis/metabolism phenotype

cardiovascular system phenotype

immune system phenotype

Genotype: Nos3tm1Unc/Nos3tm1UncB6.129P2-Nos3tm1Unc/J

mortality/aging

immune system phenotype

renal/urinary system phenotype

skeleton phenotype

hematopoietic system phenotype

growth/size/body region phenotype

cardiovascular system phenotype

respiratory system phenotype

homeostasis/metabolism phenotype

muscle phenotype

cellular phenotype

endocrine/exocrine gland phenotype

reproductive system phenotype

References

Additional - Nos3tm1Unc related

Genotyping Protocols

Breeding Considerations

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Progeny testing is not required

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

Nos3^tm1Unc

Allele Symbol: Nos3^tm1Unc

Genotype: Nos3^tm1Unc related

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd

Genotype: Nos3^tm1Unc/Nos3⁺
involves: 129P2/OlaHsd * C57BL/6J

Genotype: Nos3^tm1Unc/Nos3⁺
B6.129P2-Nos3^tm1Unc/J

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
B6.129P2-Nos3^tm1Unc

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd * C57BL/6J

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
BKS.129P2-Nos3^tm1Unc

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
involves: 129P2/OlaHsd * C57BL/6

Genotype: Nos3^tm1Unc/Nos3^tm1Unc
B6.129P2-Nos3^tm1Unc/J

Additional - Nos3^tm1Unc related