Phenotypes associated with this allele

• Allele Symbol: Nos3^tm1Plh
• Allele Name: targeted mutation 1, Paul L Huang
• Allele ID: MGI:2150145
• Summary: 14 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nos3^tm1Plh/Nos3^tm1Plh	B6.129S4-Nos3^tm1Plh	MGI:3621557
hm2	Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae	MGI:2174979
hm3	Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * C57BL/6	MGI:4366437
hm4	Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * C57BL/6J	MGI:3041154
ht5	Nos3^tm1Plh/Nos3^+	involves: 129S4/SvJae * C57BL/6	MGI:4367468
cx6	Apoe^tm1Unc/Apoe^tm1Unc Nos3^tm1Plh/Nos3^tm1Plh	B6.129-Nos3^tm1Plh Apoe^tm1Unc	MGI:4367467
cx7	Nos1^tm1Plh/Nos1^tm1Plh Nos3^tm1Plh/Nos3^tm1Plh	B6.129S4-Nos3^tm1Plh Nos1^tm1Plh	MGI:4367213
cx8	Nos3^tm1Plh/Nos3^tm1Plh Ptgs1^tm1Unc/Ptgs1^tm1Unc	involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6	MGI:4366436
cx9	Nos1^tm1Plh/Nos1^tm1Plh Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae	MGI:3789202
cx10	Nos2^tm1Mrl/Nos2^tm1Mrl Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * 129S7/SvEvBrd	MGI:3789203
cx11	Nos1^tm1Plh/Nos1^tm1Plh Nos2^tm1Mrl/Nos2^tm1Mrl Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * 129S7/SvEvBrd	MGI:3789190
cx12	Nos1^tm1Plh/Nos1^tm1Plh Nos2^tm1Mrl/Nos2^tm1Mrl Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6	MGI:4837924
cx13	Nos1^tm1Plh/Nos1^tm1Plh Nos3^tm1Plh/Nos3^tm1Plh	involves: 129S4/SvJae * C57BL/6	MGI:4367214
cx14	Nos3^tm1Plh/Nos3^tm1Plh Tg(RHO-VEGFA)V-6Camp/0	involves: 129S4/SvJae * C57BL/6J	MGI:4366931

Genotype
MGI:3621557

hm1

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: B6.129S4-Nos3^tm1Plh

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

cardiovascular system phenotype ( J:106207 )

N • unlike in mice null for Nos1 of Nos2, choroidal neovascularization following laser-induced rupture of Bruch's membrane is not significantly different from controls

abnormal induced retina neovascularization ( J:106207 )

• significant reduction in ischemia induced retinal neovascularization

abnormal cerebral blood flow rate ( J:107964 )

• L-NAME treatment fails to reduce cerebral blood flow, unlike in wild-type mice

• exposure to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA fails to alter regional cerebral blood flow, unlike in wild-type mice

abnormal systemic arterial blood pressure ( J:107964 )

• exposure to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA fails to increase mean arterial blood pressure unlike in wild-type mice

hypertension ( J:155090 )

abnormal vascular endothelial cell physiology ( J:155090 )

• endothelium dependent relaxation does not occur

nervous system

abnormal nervous system physiology ( J:107964 )

• in anesthetized mice the latency to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA induced EEG seizure is increased compared to similarly treated wild-type mice

abnormal seizure response to inducing agent ( J:107964 )

• when exposed to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA for 60 min the time to first seizure in freely moving mice is significantly longer compared to similarly treated wild-type mice

behavior/neurological

abnormal seizure response to inducing agent ( J:107964 )

• when exposed to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA for 60 min the time to first seizure in freely moving mice is significantly longer compared to similarly treated wild-type mice

vision/eye

abnormal induced retina neovascularization ( J:106207 )

• significant reduction in ischemia induced retinal neovascularization

adipose tissue

increased white adipose tissue amount ( J:155090 )

• perirenal and epididymal white adipose weights are increased

homeostasis/metabolism

abnormal circulating glucose level ( J:155090 )

• significantly increased after i.v. glucose

increased circulating triglyceride level ( J:155090 )

• elevated plasma triglycerides

decreased adiponectin level ( J:155090 )

Genotype
MGI:2174979

hm2

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae

mortality/aging

decreased survivor rate ( J:100308 )

• about 80% survival rate at 10 months of age

premature death ( J:100308 )

• about 20% die before 10 months of age

cardiovascular system

abnormal blood flow velocity ( J:112419 )

• decrease in lower thoracic aortic flow

decreased coronary flow rate ( J:60525 )

• in isolated perfused hearts

• however, coronary flow per beat is not significantly different from controls

abnormal pulmonary vascular resistance ( J:112419 )

• total pulmonary resistance and pulmonary vascular resistance are increased

abnormal systemic vascular resistance ( J:112419 )

• acetylcholine fails to decrease total systemic resistance unlike in wild-type mice

abnormal heart right ventricle pressure ( J:57624 , J:100308 )

• increase in right ventricle systolic pressure in mice exposed to chronic mild hypoxia compared to similarly treated wild-type controls (J:57624)

decreased heart rate ( J:60525 , J:100308 )

• in isolated perfused hearts (J:60525)

increased heart rate ( J:112419 )

abnormal pulmonary pressure ( J:57624 )

• in isolated whole lungs baseline pulmonary perfusion pressure is increased compared to wild-type controls

pulmonary hypertension ( J:112419 )

• mild

abnormal systemic arterial blood pressure ( J:112419 )

• acetylcholine induced decrease in systemic arterial pressure is less than in wild-type controls

increased systemic arterial blood pressure ( J:57624 )

hypertension ( J:28778 , J:60525 )

increased mean systemic arterial blood pressure ( J:55936 )

increased vasoconstriction ( J:57624 )

• enhanced hypoxic pulmonary vasoconstriction

• treatment with bradykinin results in transient vasodilation followed by sustained vasoconstriction, while in wild-type mice vasodilation is maintained

abnormal vasodilation ( J:112419 )

• acetylcholine addition fails to induce any response in pulmonary artery segments, unlike in pulmonary artery segments from wild-type mice where it induces vasodilation

decreased vasodilation ( J:28778 )

• aortic rings show no relaxation to acetylcholine as in wild-type

homeostasis/metabolism

increased susceptibility to neuronal excitotoxicity ( J:111644 )

• the size of striatal lesions induced by malonate are significantly increased compared to similarly treated controls

insulin resistance ( J:62229 )

• insulin resistance in the liver and peripheral tissues

abnormal response/metabolism to endogenous compounds ( J:112419 )

• acetylcholine induced decrease in systemic arterial pressure is less than in wild-type controls

• acetylcholine fails to decrease total systemic resistance unlike in wild-type mice

• acetylcholine addition fails to induce any response in pulmonary artery segments

muscle

muscle phenotype ( J:56948 )

N • unlike in Nos1 null mice, lower esophageal sphincter display normal electrical field stimulation (60 V, 5 Hz) induced relaxation and rebound contraction

increased vasoconstriction ( J:57624 )

• enhanced hypoxic pulmonary vasoconstriction

• treatment with bradykinin results in transient vasodilation followed by sustained vasoconstriction, while in wild-type mice vasodilation is maintained

abnormal vasodilation ( J:112419 )

• acetylcholine addition fails to induce any response in pulmonary artery segments, unlike in pulmonary artery segments from wild-type mice where it induces vasodilation

decreased vasodilation ( J:28778 )

• aortic rings show no relaxation to acetylcholine as in wild-type

nervous system

nervous system phenotype ( J:37956 )

N • despite the ability of NOS inhibitors to decrease long term potentiation, no significant decrease in long term potentiation is detected at 1 h after tetanus

increased susceptibility to neuronal excitotoxicity ( J:111644 )

• the size of striatal lesions induced by malonate are significantly increased compared to similarly treated controls

decreased neurotransmitter release ( J:119052 )

• GABA release after NMDA stimulation is significantly attenuated in the cerebral cortex, striatum and hippocampus

immune system

abnormal leukocyte adhesion ( J:55936 )

• dramatic increase in baseline leukocyte adherence

• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice

enhanced leukocyte tethering or rolling ( J:55936 )

• increase in baseline rolling

• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice

abnormal neutrophil physiology ( J:55936 )

• following thioglycollate injection neutrophil accumulation in the peritoneum is significantly enhanced compared to wild-type mice

reproductive system

abnormal penile erection ( J:89704 )

♂ • the maximal increase in intracavernous pressure induced by papaverine is reduced by 75% compared to wild-type controls

abnormal ejaculation ( J:59686 )

♂ • homozygous males have a decreased latency to ejaculation and reduced number of mounts and intromissions required for ejaculation compared to wild-type males

cellular

increased susceptibility to neuronal excitotoxicity ( J:111644 )

• the size of striatal lesions induced by malonate are significantly increased compared to similarly treated controls

abnormal leukocyte adhesion ( J:55936 )

• dramatic increase in baseline leukocyte adherence

• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice

enhanced leukocyte tethering or rolling ( J:55936 )

• increase in baseline rolling

• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice

hematopoietic system

abnormal leukocyte adhesion ( J:55936 )

• dramatic increase in baseline leukocyte adherence

• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice

enhanced leukocyte tethering or rolling ( J:55936 )

• increase in baseline rolling

• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice

abnormal neutrophil physiology ( J:55936 )

• following thioglycollate injection neutrophil accumulation in the peritoneum is significantly enhanced compared to wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
essential hypertension		DOID:10825	OMIM:145500 OMIM:603918 OMIM:604329 OMIM:607329 OMIM:608742 OMIM:610261 OMIM:610262 OMIM:610948 OMIM:611014	J:28778

Genotype
MGI:4366437

hm3

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

increased susceptibility to bacterial infection induced morbidity/mortality ( J:105005 )

• increase in mortality 24 h after infection with S. pneumoniae strain type 3

immune system

increased susceptibility to bacterial infection ( J:105005 )

• S. pneumoniae strain type 3 induced increases in intracranial pressure and cerebral spinal fluid leukocyte counts and impairment of the brain blood barrier are enhanced

• display more pronounced subarachnoid and ventricular granulocytic infiltrates 24 h after infection with S. pneumoniae strain type 3

increased susceptibility to bacterial infection induced morbidity/mortality ( J:105005 )

• increase in mortality 24 h after infection with S. pneumoniae strain type 3

cardiovascular system

abnormal lung vasculature morphology ( J:83896 )

• mice raised in mild hypoxia display a decreased vessel volume density compared to similarly raised wild-type controls

abnormal heart left ventricle morphology ( J:75645 )

• left ventricular chamber size is reduced

heart left ventricle hypertrophy ( J:75645 )

• age related

decreased cardiac muscle contractility ( J:75645 )

• sarcomere shortening in response to a beta3-adrenergic agonist is absent

increased cardiac muscle contractility ( J:75645 )

• increase in the beta-adrenergic inotropic responses

increased heart rate ( J:75645 )

• mild

abnormal myocardial fiber physiology ( J:75645 )

• Ca2+ transients in response to a beta3-adrenergic agonist are absent

increased systemic arterial systolic blood pressure ( J:75645 , J:108540 )

• in male, but not female, mice (J:108540)

abnormal blood vessel physiology ( J:75645 , J:108540 )

• arterial elastance is increased (J:75645)

• relaxation of mesenteric arteries and the aorta of acetylcholine-treat male mice is inhibited unlike similarly treated female and wild-type mice (J:108540)

abnormal induced retina neovascularization ( J:66540 )

• following exposure to 75% oxygen from P7 to P12, extraretinal neovascularization upon return to room air is significantly decreased compared to similarly treated wild-type mice

abnormal vascular wound healing ( J:119617 , J:139343 )

• neointimal formation after cuff injury is increased compared to wild-type controls (J:119617)

• neointimal formation after cuff injury is increased in males relative to females (J:119617)

• neointimal formation after cuff injury is decreased in pregnant females compared to non pregnant females; however, the level in mutants is still increased compared to wild-type (J:119617)

• at day 28 following femoral artery resection limb perfusion remains impaired unlike in wild-type mice (J:139343)

• capillary density remains reduced for a longer period of time following femoral artery resection (J:139343)

• VEGF treatment fails to improve angiogenesis following femoral artery resection (J:139343)

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:133437 )

N • despite increase in visceral fat, no change in triacylglycerol levels in the blood are detected

abnormal vascular wound healing ( J:119617 , J:139343 )

• neointimal formation after cuff injury is increased compared to wild-type controls (J:119617)

• neointimal formation after cuff injury is increased in males relative to females (J:119617)

• neointimal formation after cuff injury is decreased in pregnant females compared to non pregnant females; however, the level in mutants is still increased compared to wild-type (J:119617)

• at day 28 following femoral artery resection limb perfusion remains impaired unlike in wild-type mice (J:139343)

• capillary density remains reduced for a longer period of time following femoral artery resection (J:139343)

• VEGF treatment fails to improve angiogenesis following femoral artery resection (J:139343)

decreased circulating glucose level ( J:133437 )

increased circulating estradiol level ( J:89702 )

• following superovulation the plasma estradiol level is significantly higher in homozygous mutant females compared to wild-type mice

decreased circulating insulin level ( J:133437 )

decreased prostaglandin level ( J:108540 )

decreased physiological sensitivity to xenobiotic ( J:108540 )

• relaxation of mesenteric arteries and the aorta of acetylcholine-treat male mice is inhibited unlike similarly treated female and wild-type mice

reproductive system

abnormal primary polar body morphology ( J:89702 )

♀ • oocytes with an unusually large first polar body are observed

small ovary ( J:89702 )

♀ • ovaries from homozygous mutant females are significantly smaller than those from wild-type females following stimulation by exogenous gonadotropins

abnormal ovary physiology ( J:89702 )

♀

abnormal oogenesis ( J:89702 )

♀

abnormal oocyte morphology ( J:89702 )

♀ • a variety of abnormal characteristics noted including enlarged first polar body, cytoplasmic cleavage, blebbing, premature release of the second polar body and cell division

abnormal female meiosis ( J:89702 )

♀ • many of the arrested and abnormal oocytes are also dying

♀ • fewer oocytes from mutant females reach metaphase II of meiosis but instead remain in metaphase I or become abnormal with an enlarged first polar body, cytoplasmic cleavage, blebbing, and/or premature release of the second polar body

abnormal superovulation ( J:58361 )

♀ • the number of ovarian rupture sites stimulated by exogenous gonadotropins is decreased in mutant females compared to wild-type mice

decreased superovulation rate ( J:89702 )

♀ • the number of oocytes released following stimulation by exogenous gonadotropins is decreased in mutant females compared to wild-type mice

♀ • mutants produced 62% fewer oocytes than controls after superovualtion

short estrous cycle ( J:58361 )

♀ • oestrus cycle length and individual variability in cycle length is reduced in homozygous mutant females compared to C57BL/6J wild-type mice

reduced female fertility ( J:89702 )

♀

decreased litter size ( J:58361 , J:89702 )

• homozygous mutant females have a smaller average litter size compared to wild-type mice (J:58361)

• a lower percentage of pups are weaned by homozygous mutant females compared to wild-type mice (J:58361)

• matings between homozygous mutants produce smaller litters size compared to matings between wild-type mice or heterozygous mice (J:89702)

• a lower percentage of pups born to homozygous mutant females survive to weaning (J:89702)

• litters from homozygous mutant females have a decreased ratio of female to male pups (J:89702)

endocrine/exocrine glands

small ovary ( J:89702 )

♀ • ovaries from homozygous mutant females are significantly smaller than those from wild-type females following stimulation by exogenous gonadotropins

abnormal ovary physiology ( J:89702 )

♀

muscle

heart left ventricle hypertrophy ( J:75645 )

• age related

decreased cardiac muscle contractility ( J:75645 )

• sarcomere shortening in response to a beta3-adrenergic agonist is absent

increased cardiac muscle contractility ( J:75645 )

• increase in the beta-adrenergic inotropic responses

vision/eye

abnormal induced retina neovascularization ( J:66540 )

• following exposure to 75% oxygen from P7 to P12, extraretinal neovascularization upon return to room air is significantly decreased compared to similarly treated wild-type mice

abnormal eye physiology ( J:66540 )

• decrease capillary loss following exposure to 75% oxygen from P7 to P9 compared to similarly treated wild-type mice

• levels of nitrotyrosine in mutants exposed to hyperoxic conditions are not significantly increased compared to room air controls, unlike in wild-type mice

limbs/digits/tail

abnormal femur morphology ( J:67336 )

• bone volume is decreased at 6 and 9 weeks of age

• mean trabecular thickness, osteoid surface, osteoblast surface, mineralizing surface, and eroded surface are reduced at 6 weeks of age

short femur ( J:67336 )

• detected at 6, 9 and 18 weeks of age

renal/urinary system

abnormal renal glomerulus morphology ( J:67336 )

• mild glomerular hypercellularity is seen in about 10% of mice at 9 weeks of age

skeleton

abnormal osteoblast physiology ( J:67336 )

• after 5 days in culture the number of osteoblasts is significantly reduced compared to wild-type cells

• in culture osteoblasts have decreased alkaline phosphatase activity and form fewer mineralized nodules compared to wild-type cells

• stimulation with 17-beta-estradiol fails to stimulate osteoblast proliferation in culture

• cytokine (TGFB) stimulated migration is attenuated in culture osteoblasts compared to wild-type cells

abnormal femur morphology ( J:67336 )

• bone volume is decreased at 6 and 9 weeks of age

• mean trabecular thickness, osteoid surface, osteoblast surface, mineralizing surface, and eroded surface are reduced at 6 weeks of age

short femur ( J:67336 )

• detected at 6, 9 and 18 weeks of age

abnormal long bone epiphyseal plate morphology ( J:67336 )

• in the femur, osteoid surface, mineralizing surface, and osteoblast surface are reduced at 6 weeks of age

decreased bone mineral density ( J:67336 )

• at 8 weeks of age, femoral/pelvic, spinal, and whole body total bone mineral density are reduced

• however, at 12 weeks of age no significant difference in bone mineral density is detected

abnormal trabecular bone thickness ( J:67336 )

• mean trabecular thickness in the femur is reduced at 6 and 18 weeks of age

abnormal bone mineralization ( J:67336 )

• at 6 weeks of age the mineral apposition rate is modestly decreased in the femur

growth/size/body

heart left ventricle hypertrophy ( J:75645 )

• age related

decreased body weight ( J:83896 )

• at P11 mice raised in 16% oxygen (mild hypoxia) weigh less than similarly raised wild-type controls

increased body weight ( J:133437 )

• at 1 year of age

respiratory system

abnormal lung vasculature morphology ( J:83896 )

• mice raised in mild hypoxia display a decreased vessel volume density compared to similarly raised wild-type controls

abnormal pulmonary alveolus morphology ( J:83896 )

• mice raised in mild hypoxia display an increased mean lung intercept indicating an increase in intra-alveolar distance and a decreased radial alveolar count compared to similarly raised wild-type controls

behavior/neurological

abnormal associative learning ( J:101302 )

• less helpless (reduced escape latency, fewer failures, and improved avoidance of the aversive stimulus) in a learned helplessness paradigm

• differences are not the result of differences in pain sensitivity, activity level, or anxiety level

nervous system

abnormal neuronal precursor proliferation ( J:101302 )

• significant decrease in progenitor cell proliferation

abnormal dentate gyrus morphology ( J:101302 )

• the granule cell layer is increased in volume

abnormal neuron morphology ( J:101302 )

• decrease in the percentage of pyknotic cells in the brain; however, the number of degenerating cells (detected by Fluoro-Jade B staining) is increased

adipose tissue

abnormal adipose tissue amount ( J:133437 )

• increase in the amount of visceral fat at 1 year of age

liver/biliary system

abnormal liver morphology ( J:133437 )

• increased accumulation of glycogen is seen predominantly in zone 1 of the liver

abnormal hepatocyte morphology ( J:133437 )

• hepatocytes in zone one (closest to the artery) contain fewer mitochondria, while hepatocytes in zone 3 contain more mitochondria compared to wild-type cells from the same zone

hepatic steatosis ( J:133437 )

• massive fat deposition is seen in zone 3 of the liver

abnormal liver physiology ( J:133437 )

• the ratio of cytosolic citrate synthase activity to NADH-cytochrome c oxidoreductase (KI+III) activity is elevated in liver homogenates

cellular

abnormal oocyte morphology ( J:89702 )

♀ • a variety of abnormal characteristics noted including enlarged first polar body, cytoplasmic cleavage, blebbing, premature release of the second polar body and cell division

abnormal primary polar body morphology ( J:89702 )

♀ • oocytes with an unusually large first polar body are observed

abnormal neuronal precursor proliferation ( J:101302 )

• significant decrease in progenitor cell proliferation

abnormal osteoblast physiology ( J:67336 )

• after 5 days in culture the number of osteoblasts is significantly reduced compared to wild-type cells

• in culture osteoblasts have decreased alkaline phosphatase activity and form fewer mineralized nodules compared to wild-type cells

• stimulation with 17-beta-estradiol fails to stimulate osteoblast proliferation in culture

• cytokine (TGFB) stimulated migration is attenuated in culture osteoblasts compared to wild-type cells

maternal effect ( J:89702 )

• 42% of pups born to homozygous females are dead by weaning

Genotype
MGI:3041154

hm4

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

homeostasis/metabolism

increased circulating estradiol level ( J:89542 )

• the preovulatory peak of estradiol is 5-fold higher and occurs later in the cycle in homozygous mutant females compared to 129/SvEv wild-type mice

increased circulating progesterone level ( J:89542 )

• the diestrus progesterone level is 3-fold higher in homozygous mutant females compared to 129/SvEv wild-type mice

reproductive system

decreased ovulation rate ( J:89542 )

♀ • the number of oocytes released is significantly reduced in homozygous mutant females compared to 129/SvEv wild-type mice

♀ • during proestrus fewer large antral follicles and during diestrus fewer newly formed corpora lutea are found in ovaries from homozygous mutant females compared to 129/SvEv wild-type mice

prolonged diestrus ( J:89542 )

♀

prolonged estrous cycle ( J:89542 )

♀ • oestrus cycle length is increased in homozygous mutant females compared to 129/SvEv wild-type mice as the result of an extended diestrus

digestive/alimentary system

digestive/alimentary phenotype ( J:64225 )

N • unlike mice null for Nos1, the sizes of the esophagus, stomach and duodenum are similar to wild-type controls and no defect is detected in gastric emptying

Genotype
MGI:4367468

ht5

• Allelic Composition: Nos3^tm1Plh/Nos3⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

respiratory system

abnormal pulmonary alveolus morphology ( J:83896 )

• mice raised in mild hypoxia display an increased mean lung intercept indicating an increase in intra-alveolar distance and a decreased radial alveolar count compared to similarly raised wild-type controls

• these changes are less severe than those in homozygous mutant mice

Genotype
MGI:4367467

cx6

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: B6.129-Nos3^tm1Plh Apoe^tm1Unc

cardiovascular system

increased susceptibility to atherosclerosis ( J:103306 )

• increase in lesion area relative to Apoe single mutants when fed a Western type diet

• unlike in Apoe single mutants no difference in lesion area is seen at 4 months of age in double mutants fed a Western type diet

• all mice show distal coronary arteriosclerosis associated with perivascular and endomyocardial fibrosis and endomyocardial scars consistent with nontransmural infarction

aortic dissection ( J:103306 )

• 2 of 12 mice fed a Western type diet for 16 weeks developed acute Stanford type B aortic dissections that are not seen in Apoe single mutants

thick interventricular septum ( J:103306 )

• thickening of the interventricular septum is seen in double mutants fed a Western type diet for 16 weeks

increased heart left ventricle posterior wall thickness ( J:103306 )

• thickening of the LV posterior wall is seen in double mutants fed a Western type diet for 16 weeks

dilated heart left ventricle ( J:103306 )

• 2 of 10 mice fed a Western type diet for 16 weeks displayed massive dilation of the left ventricle

cardiac fibrosis ( J:103306 )

• all mice show distal coronary arteriosclerosis associated with perivascular and endomyocardial fibrosis and endomyocardial scars consistent with nontransmural infarction

increased susceptibility to induced aneurysm formation ( J:103306 )

• 3 of 12 mice fed a Western type diet for 16 weeks developed atherosclerotic suprarenal abdominal aortic aneurysms that are not seen in Apoe single mutants

decreased cardiac muscle contractility ( J:103306 )

• decrease in fractional shortening in double mutants fed a Western type diet for 16 weeks

increased mean systemic arterial blood pressure ( J:103306 )

• increased relative to wild-type controls and Apoe single mutants but similar to Nos3 single mutants

muscle

decreased cardiac muscle contractility ( J:103306 )

• decrease in fractional shortening in double mutants fed a Western type diet for 16 weeks

Genotype
MGI:4367213

cx7

• Allelic Composition: Nos1^tm1Plh/Nos1^tm1Plh; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: B6.129S4-Nos3^tm1Plh Nos1^tm1Plh

cardiovascular system

heart left ventricle hypertrophy ( J:129064 )

• myocyte hypertrophy is detected by 4-5 months of age

• hypertrophy becomes more severe with age

cardiac interstitial fibrosis ( J:129064 )

• areas of focal interstitial fibrosis are seen in old (14-15 months of age) mice

increased cardiac muscle contractility ( J:129064 )

• prior to the development of frank left ventricular hypertrophy indices of myocardial contractility are elevated

• indices of contractility are also increased in old mice

• ejection fraction is increased in old mice

abnormal cardiac muscle relaxation ( J:129064 )

• passive diastolic relaxation appears impaired based on an increase in the time to peak filling

decreased left ventricle diastolic pressure ( J:129064 )

• decrease in left ventricular end diastolic pressure in young mice

increased heart rate ( J:129064 )

increased systemic arterial systolic blood pressure ( J:129064 )

• in young and old mice

muscle

heart left ventricle hypertrophy ( J:129064 )

• myocyte hypertrophy is detected by 4-5 months of age

• hypertrophy becomes more severe with age

increased cardiac muscle contractility ( J:129064 )

• prior to the development of frank left ventricular hypertrophy indices of myocardial contractility are elevated

• indices of contractility are also increased in old mice

• ejection fraction is increased in old mice

abnormal cardiac muscle relaxation ( J:129064 )

• passive diastolic relaxation appears impaired based on an increase in the time to peak filling

growth/size/body

heart left ventricle hypertrophy ( J:129064 )

• myocyte hypertrophy is detected by 4-5 months of age

• hypertrophy becomes more severe with age

cellular

cardiac interstitial fibrosis ( J:129064 )

• areas of focal interstitial fibrosis are seen in old (14-15 months of age) mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertrophic cardiomyopathy		DOID:11984		J:129064

Genotype
MGI:4366436

cx8

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh; Ptgs1^tm1Unc/Ptgs1^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

cardiovascular system

increased systemic arterial systolic blood pressure ( J:108540 )

• in male, but not female, mice

abnormal blood vessel physiology ( J:108540 )

• relaxation of mesenteric arteries and the aorta of acetylcholine-treat male mice is inhibited unlike similarly treated female and wild-type mice

• male mice fail to exhibit a bradykinin-dependent decrease in blood pressure unlike similarly treated female mice

homeostasis/metabolism

decreased prostaglandin level ( J:108540 )

decreased physiological sensitivity to xenobiotic ( J:108540 )

• relaxation of mesenteric arteries and the aorta of acetylcholine-treat male mice is inhibited unlike similarly treated female and wild-type mice

• male mice fail to exhibit a bradykinin-dependent decrease in blood pressure unlike similarly treated female mice

Genotype
MGI:3789202

cx9

• Allelic Composition: Nos1^tm1Plh/Nos1^tm1Plh; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae

mortality/aging

decreased survivor rate ( J:100308 )

• 60-80% survival rate at 10 months of age

premature death ( J:100308 )

• about 20-40% die before 10 months of age

reproductive system

reduced fertility ( J:100308 )

• slight reduction in the number of offspring produced from breeding pairs

cardiovascular system

decreased heart rate ( J:100308 )

increased systemic arterial systolic blood pressure ( J:100308 )

homeostasis/metabolism

increased blood osmolality ( J:100308 )

increased blood urea nitrogen level ( J:100308 )

decreased urine sodium level ( J:100308 )

decreased urine osmolality ( J:100308 )

behavior/neurological

polydipsia ( J:100308 )

nervous system

nervous system phenotype ( J:37956 )

N • unlike long term potentiation, long term depression and paired pulse facilitation are not significantly different from controls and no significant abnormalities in hippocampal morphology are detected

abnormal sensory neuron innervation pattern ( J:61144 )

• at P21 the ipsilateral retinocollicular projections are spread across cover more of the medio-lateral axis of and extend further caudally in the superior colliculus rather than being confined to the most medial and rostral regions as in wild-type controls

• at P28, ipsilateral retinocollicular projections remain more broadly distributed in the superior colliculus

• however, by P90 ipsilateral retinocollicular projections resemble those in wild-type controls indicating a delay in refinement rather than a block

reduced long-term potentiation ( J:37956 )

• unlike in either single homozygote, hippocampal long term potentiation is significantly reduced at 1 h after tetanus

• however, long term potentiation in the stratum oriens is not significantly different from controls

renal/urinary system

decreased urine sodium level ( J:100308 )

decreased urine osmolality ( J:100308 )

polyuria ( J:100308 )

Genotype
MGI:3789203

cx10

• Allelic Composition: Nos2^tm1Mrl/Nos2^tm1Mrl; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * 129S7/SvEvBrd

mortality/aging

decreased survivor rate ( J:100308 )

• 60-80% survival rate at 10 months of age

premature death ( J:100308 )

• about 20-40% die before 10 months of age

reproductive system

reduced fertility ( J:100308 )

• slight reduction in the number of offspring produced from breeding pairs

cardiovascular system

decreased heart rate ( J:100308 )

increased systemic arterial systolic blood pressure ( J:100308 )

homeostasis/metabolism

increased blood osmolality ( J:100308 )

• plasma osmolality is increased

increased blood urea nitrogen level ( J:100308 )

decreased urine sodium level ( J:100308 )

decreased urine osmolality ( J:100308 )

renal/urinary system

decreased urine sodium level ( J:100308 )

decreased urine osmolality ( J:100308 )

polyuria ( J:100308 )

behavior/neurological

polydipsia ( J:100308 )

Genotype
MGI:3789190

cx11

• Allelic Composition: Nos1^tm1Plh/Nos1^tm1Plh; Nos2^tm1Mrl/Nos2^tm1Mrl; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * 129S7/SvEvBrd

Renal tubular apoptosis, regeneration, glomerulosclerosis and glomerular thrombus formation in Nos1^tm1Plh/Nos1^tm1Plh Nos2^tm1Mrl/Nos2^tm1Mrl Nos3^tm1Plh/Nos3^tm1Plh mice

mortality/aging

decreased survivor rate ( J:100308 )

• only 3 of 13 mutants survive to 10 months of age

premature death ( J:100308 )

• only 3 of 13 mutants survive to 10 months of age

reproductive system

reduced fertility ( J:100308 )

• the number of offspring produced from breeding pairs is significantly smaller than in wild-type

cardiovascular system

abnormal coronary artery morphology ( J:100308 )

• all mutants that die show wall thickening, perivascular fibrosis, and adventitial mast cell infiltration of the coronary arteries

visceral vascular congestion ( J:100308 )

• 2 mutants that die within 10 months of age, have pulmonary and liver congestion

liver vascular congestion ( J:100308 )

• in 2 mutants that die within 10 months of age

pulmonary vascular congestion ( J:100308 )

• in 2 mutants that die within 10 months of age

decreased heart rate ( J:100308 )

• heart rate is significantly lower than in wild-type, but similar to that of single Nos3 homozygotes, double Nos1/Nos3 homozygotes, and double Nos2/Nos3 homozygotes

increased systemic arterial blood pressure ( J:100308 )

hypertension ( J:100308 )

• hypertension is similar to single Nos3 homozygotes, double Nos1/Nos3 homozygotes, and double Nos2/Nos3 homozygotes

increased systemic arterial systolic blood pressure ( J:100308 )

• systolic blood pressure is significantly higher in mutants than wild-type under conscious conditions

congestive heart failure ( J:100308 )

• the two mutants with pulmonary and liver congestion and acute renal tubular necrosis exhibit acute circulatory failure

homeostasis/metabolism

increased circulating creatinine level ( J:100308 )

• plasma concentrations of creatinine tend to be higher

increased blood osmolality ( J:100308 )

• plasma osmolality is increased

increased blood urea nitrogen level ( J:100308 )

• plasma concentrations of urea nitrogen are higher

increased circulating alkaline phosphatase level ( J:150159 )

• serum concentration is increased

abnormal glomerular capillary thrombosis ( J:100308 )

• glomerular thrombus formation

dehydration ( J:100308 )

abnormal nitric oxide homeostasis ( J:100308 )

• mutants exhibit only 2.4% and 3.6% of normal plasma and urinary NO levels, respectively

decreased urine sodium level ( J:100308 )

increased prostaglandin level ( J:100308 )

• renal prostacyclin levels are significantly higher in 1 week old mutants than in wild-type

decreased urine osmolality ( J:100308 )

renal/urinary system

renal tubular necrosis ( J:100308 )

• 2 mutants that die within 10 months of age have acute renal tubular necrosis

decreased urine sodium level ( J:100308 )

decreased urine osmolality ( J:100308 )

abnormal renal glomerulus morphology ( J:100308 )

• glomerular thrombus formation

• renal tubular lesions are seen predominantly in distal and collecting tubules than in proximal tubules

glomerulosclerosis ( J:100308 )

abnormal kidney physiology ( J:100308 )

• renal responsiveness to the anti-diuretic hormone, vasopressin, is reduced compared to wild-type, although central vasopressin release in unchanged

• impaired renal cAMP production

increased renal tubule apoptosis ( J:100308 )

polyuria ( J:100308 )

• hypotonic polyuria

behavior/neurological

polydipsia ( J:100308 )

digestive/alimentary system

pyloric sphincter hypertrophy ( J:100308 )

• pyloric sphincter hypertrophy

enlarged stomach ( J:100308 )

• 3 of 5 mutants show enlargement of the stomach

liver/biliary system

liver vascular congestion ( J:100308 )

• in 2 mutants that die within 10 months of age

respiratory system

pulmonary vascular congestion ( J:100308 )

• in 2 mutants that die within 10 months of age

skeleton

abnormal bone structure ( J:150159 )

increased osteoclast cell number ( J:150159 )

increased bone mineral density ( J:150159 )

• at all time points

• increases slightly at 12 weeks of age

abnormal trabecular bone morphology ( J:150159 )

• trabecular bone in the proximal tibia is increased

abnormal skeleton physiology ( J:150159 )

abnormal osteoclast physiology ( J:150159 )

• increased osteoclast function

• higher in females than in males

abnormal bone mineralization ( J:150159 )

• bone formation rate and mineral apposition rate are increased

• higher in females than in males

hematopoietic system

increased osteoclast cell number ( J:150159 )

abnormal osteoclast physiology ( J:150159 )

• increased osteoclast function

• higher in females than in males

immune system

increased osteoclast cell number ( J:150159 )

abnormal osteoclast physiology ( J:150159 )

• increased osteoclast function

• higher in females than in males

muscle

pyloric sphincter hypertrophy ( J:100308 )

• pyloric sphincter hypertrophy

cellular

increased renal tubule apoptosis ( J:100308 )

renal tubular necrosis ( J:100308 )

• 2 mutants that die within 10 months of age have acute renal tubular necrosis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
nephrogenic diabetes insipidus		DOID:12387		J:100308

Genotype
MGI:4837924

cx12

• Allelic Composition: Nos1^tm1Plh/Nos1^tm1Plh; Nos2^tm1Mrl/Nos2^tm1Mrl; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6

mortality/aging

premature death ( J:155090 )

• 85% of males die within 11 months whereas only 35-40% of males of any double homozygous genotype die at that time point

cardiovascular system

abnormal cardiovascular system morphology ( J:155090 )

arteriosclerosis ( J:155090 )

• in most of the vasculature

• lipid accumulation in the aorta

perivascular fibrosis ( J:155090 )

• perivascular fibrosis of large epicardial coronary arteries and renal arteries

thick ventricular wall ( J:155090 )

• anterior and posterior ventricular walls are thickened

abnormal cardiovascular system physiology ( J:155090 )

hypertension ( J:155090 )

abnormal vascular endothelial cell physiology ( J:155090 )

• endothelium dependent relaxation lacking

abnormal vascular wound healing ( J:155090 )

• no vascular lesions in 2 month old males

• significant neointimal formation at 5 months

• medial thickening at 5 months

adipose tissue

increased white adipose tissue amount ( J:155090 )

• perirenal and epididymal white adipose weights are increased

homeostasis/metabolism

abnormal vascular wound healing ( J:155090 )

• no vascular lesions in 2 month old males

• significant neointimal formation at 5 months

• medial thickening at 5 months

abnormal circulating glucose level ( J:155090 )

• significantly increased after i.v. glucose

increased circulating LDL cholesterol level ( J:155090 )

increased circulating triglyceride level ( J:155090 )

• elevated plasma triglycerides

decreased adiponectin level ( J:155090 )

Genotype
MGI:4367214

cx13

• Allelic Composition: Nos1^tm1Plh/Nos1^tm1Plh; Nos3^tm1Plh/Nos3^tm1Plh
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

decreased survivor rate ( J:129064 )

• survival at 20 months is reduced compared to Nos3 or Nos1 single mutant mice

premature death ( J:129064 )

• survival at 20 months is reduced compared to Nos3 or Nos1 single mutant mice

• the relative risk of death by 20 months of age is increased 7.3 fold compared to Nos3 single mutants and 3.0 fold compared to Nos1 single mutants

• mortality is increased in males compared to females

cardiovascular system

heart left ventricle hypertrophy ( J:75645 )

• develop age related concentric remodeling with marked increase in relative wall thickness

• increase in wall thickness and decrease in systolic and diastolic dimensions with age

decreased cardiac muscle contractility ( J:75645 )

• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve

increased cardiac muscle contractility ( J:75645 )

• increase in basal contractility

• hypertrophy is associated with hypercontractility

abnormal cardiac muscle relaxation ( J:75645 )

• hypertrophy is associated with increased diastolic stiffness

increased heart rate ( J:75645 )

• relative to wild-type mice and Nos3 single mutants

increased systemic arterial systolic blood pressure ( J:75645 )

• identical to that in Nos3 single mutants

muscle

heart left ventricle hypertrophy ( J:75645 )

• develop age related concentric remodeling with marked increase in relative wall thickness

• increase in wall thickness and decrease in systolic and diastolic dimensions with age

decreased cardiac muscle contractility ( J:75645 )

• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve

increased cardiac muscle contractility ( J:75645 )

• increase in basal contractility

• hypertrophy is associated with hypercontractility

abnormal cardiac muscle relaxation ( J:75645 )

• hypertrophy is associated with increased diastolic stiffness

growth/size/body

heart left ventricle hypertrophy ( J:75645 )

• develop age related concentric remodeling with marked increase in relative wall thickness

• increase in wall thickness and decrease in systolic and diastolic dimensions with age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertrophic cardiomyopathy		DOID:11984		J:129064

Genotype
MGI:4366931

cx14

• Allelic Composition: Nos3^tm1Plh/Nos3^tm1Plh; Tg(RHO-VEGFA)V-6Camp/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

cardiovascular system

abnormal angiogenesis ( J:106207 )

• compared to mice carrying Tg(RHO-VEGFA)V-6Camp and heterozygous for Nos3^tm1Plh neovascularization of the retina is significantly reduced