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Phenotypes Associated with This Genotype
Genotype
MGI:3618597
Allelic
Composition
Nos3tm1Unc/Nos3tm1Unc
Genetic
Background
B6.129P2-Nos3tm1Unc/J
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Nos3tm1Unc mutation (6 available); any Nos3 mutation (56 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• about 40% die within the first hour of birth
• 85% of mice die by P10 compared with 13% of wild-type mice

growth/size/body
• 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
• however, homozygotes show no significant differences in baseline heart weight or myocyte size relative to wild-type mice
• fetuses from E18 to term demonstrate slight growth retardation (J:98913)
• 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. (J:140819)

cardiovascular system
• after remnant kidney surgery, homozygotes exhibit a significantly greater endothelial cell loss than similarly-treated wild-type controls
• 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
• 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
• severe with focal alveolar edema
• 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
• E19.5 lungs show dramatic decrease of arteriolar branches and regions of marked capillary hypoperfusion
• diastolic dimension is increased compared to in wild-type mice
• membranous and muscular ventricular defects in 6 of 10 mice compared with 1 of 10 atrial septal defects in 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 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
• however, homozygotes show no significant differences in baseline heart weight or myocyte size relative to wild-type mice
• high incidence (5 of 12) bicuspid aortic valves, however do not exhibit aortic coarctation
• ventricular hypertrophy
• after remnant kidney surgery, homozygotes develop microaneurysms unlike similarly-treated wild-type controls
• E16 lungs show scattered areas of parenchymal and interlobar hemorrhages
• 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
• in fetal atrioventricular endothelial cushions, septum primum and right and left ventricular myocardium
• at E12.5, E15.5 and P1 in the myocardium
• 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
• 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

respiratory system
• E16 lungs show scattered areas of parenchymal and interlobar hemorrhages
• 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
• 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
• severe with focal alveolar edema
• observe an increase in markedly swollen glycogen laden pneumocytes protruding into airspaces compared to wild-type
• no evidence of lamellar bodies in type II pneumocytes
• pups exhibit marked septal thickening
• some newborns exhibit severe respiratory distress
• lack of surfactant in bronchial alveolar lavage fluid

homeostasis/metabolism
• after remnant kidney surgery, homozygotes exhibit a significantly higher increase in BUN levels relative to similarly-treated wild-type controls
• serum osteocalcin (BGLAP) levels are significantly higher in sham treated compared to wild-type sham mice at baseline, 14 weeks and remain higher
• serum TRAP5b (ACP5) concentrations are significantly higher in sham treated compared wild-type sham treated mice at all time points
• after remnant kidney surgery, homozygotes exhibit a significantly higher increase in serum creatinine levels relative to similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes develop intraluminal thrombi unlike similarly-treated wild-type controls
• some newborns show varying levels of cyanosis
• after remnant kidney surgery, homozygotes exhibit a significantly higher increase in urinary albumin excretion relative to similarly-treated wild-type controls

muscle
• 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
• in fetal atrioventricular endothelial cushions, septum primum and right and left ventricular myocardium
• at E12.5, E15.5 and P1 in the myocardium
• after remnant kidney surgery, homozygotes exhibit increased mesangial proliferation relative to similarly-treated wild-type controls
• 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 controls
• in two week old mice based upon TUNEL staining and the presence of Apoptotic nuclei with a dense punctate appearance
• in 2 week old mice, as pyknotic nuclei and vacuolated cytoplasm are observed
• after remnant kidney surgery, homozygotes exhibit a 36% reduction of proliferating endothelial cells in cortical peritubular capillaries relative to similarly-treated wild-type controls
• serum osteocalcin (BGLAP) levels are significantly higher in sham compared wit wild-type sham mice at baseline and at 14 wk and remained higher
• 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

endocrine/exocrine glands
• 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
• 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)
• on day 0.5 of estrous cycle, mutant ovaries are significantly smaller than wild-type

reproductive system
• 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
• 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)
• on day 0.5 of estrous cycle, mutant ovaries are significantly smaller than wild-type
• female homozygotes display a higher rate of anovulation than wild-type controls (48.3 +/- 7.3% versus 29.7 +/- 6.3, respectively)
• female homozygotes display a lower ovulation rate than wild-type controls (9.7 +/- 1.2% versus 14.2 +/- 1.2%, respectively)
• 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
• 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
• 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)
• 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

immune system
• serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points
• 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
• 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
• 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 controls
• in two week old mice based upon TUNEL staining and the presence of Apoptotic nuclei with a dense punctate appearance
• after remnant kidney surgery, homozygotes exhibit a 36% reduction of proliferating endothelial cells in cortical peritubular capillaries relative to similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes exhibit a significantly higher increase in urinary albumin excretion relative to similarly-treated wild-type controls
• 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
• in 80% of adult freshly isolated kidneys indentations are observed, indicating zones of parenchymal scarring
• 4% of glomeruli outside scarred area exhibit loss of cellularity and vasculature, a hyalinization like appearance
• after remnant kidney surgery, homozygotes exhibit a 44% increase in tubulointerstitial injury relative to similarly-treated wild-type controls
• glomeruli within scarred areas are considerably smaller than wild-type
• after remnant kidney surgery, homozygotes exhibit a significantly greater endothelial cell loss than similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes exhibit increased mesangial proliferation relative to similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes exhibit increased matrix deposition in some glomeruli unlike similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes develop mesangiolysis unlike similarly-treated wild-type controls
• within scarred areas (J:117046)
• after remnant kidney surgery, homozygotes develop significant glomerulosclerosis, unlike similarly-treated wild-type controls (J:148626)
• after remnant kidney surgery, homozygotes exhibit a 46% increase in glomerular collagen IV deposition relative to similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes develop significantly greater glomerular hypertrophy than similarly-treated wild-type controls
• frequently a large lipid droplet is observed with Bowman's capsule and the adjacent matrix
• after remnant kidney surgery, homozygotes exhibit more severe sloughing , vacuolization and nuclear exfoliation of tubular epithelial cells relative to similarly-treated wild-type controls
• thin strands of connective tissue distributed loosely within the interglomerular interstitium (J:117046)
• after remnant kidney surgery, homozygotes exhibit a 38% increase in collagen III deposition in the tubulointerstitium relative to similarly-treated wild-type controls (J:148626)
• within scarred areas
• the glomeruli often display no clear connection to typical large-diameter proximal tubules
• after remnant kidney surgery, homozygotes exhibit more severe tubular dilatation than similarly-treated wild-type controls
• after remnant kidney surgery, homozygotes exhibit more severe tubular cast formation than similarly-treated wild-type controls
• degeneration of the glomerular core components is common within the scarred zones
• in 2 week old mice, as pyknotic nuclei and vacuolated cytoplasm are observed
• after remnant kidney surgery, homozygotes exhibit significantly worse renal function relative to similarly-treated wild-type controls

skeleton
• serum osteocalcin (BGLAP) levels are significantly higher in sham compared wit wild-type sham mice at baseline and at 14 wk and remained higher
• serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points
• exagerated BMD decrease in ovariectomized mice
• between 10-20 weeks post sham-operation compared to sham-operated wild-type
• significantly greater cortical thickness in sham operated mice compared to sham operated wild-type mice

hematopoietic system
• serum concentrations of TRAP5b (ACP5) are significantly higher in sham treated compared to wild-type sham treated mice at all time points


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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last database update
03/19/2024
MGI 6.23
The Jackson Laboratory