Analysis Tools
integument
| N |
• no calcification occurs in the fibrous capsule surrounding the muzzle vibrissae
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Allele Symbol Allele Name Allele ID |
Tg(Tagln-cre)1Her transgene insertion 1, Joachim Herz MGI:2446975 |
| Summary |
45 genotypes |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no calcification occurs in the fibrous capsule surrounding the muzzle vibrissae
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• most mice die within 2 days of birth with few surviving beyond 4 weeks
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• most mice die within 2 days of birth with few surviving beyond 4 weeks
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• multifoci
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• absent or incompletely formed bile ducts near the portal veins
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• biliary epithelial cells are unable to organize into tubules; portal vein mesenchyme is reduced
• epithelial cells fail to aggregate
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• accumulation of bile in liver parenchyma
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• total and conjugated
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• at P25
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• at birth and in mice that survive beyond 4 weeks, worsening over time
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• multifoci
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• absent or incompletely formed bile ducts near the portal veins
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• biliary epithelial cells are unable to organize into tubules; portal vein mesenchyme is reduced
• epithelial cells fail to aggregate
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Alagille syndrome | DOID:9245 |
OMIM:118450 OMIM:610205 |
J:166890 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• medial thickness is doubled with an increase in the number of cell nuclei
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• increase in the number of disruptions of the elastic layers
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• freshly isolated cells are more epithelioid shaped compared to the spindled shaped cells from control mice
• alpha-actin filaments are less abundant and often disrupted in quiescent smooth muscle cells
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• aortic smooth muscle cells challenged with PDGF-bb display more rapid alpha-actin filament disassembly and fillapodial extension and enhanced proliferation and migration compared to controls
• cultured aortic smooth muscle cells show enhanced serum induced cell growth
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• aortic rings mice fail to reach the 50% level of force generation at any concentration of KCl and phenylephrine tested
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• increase in neointimal formation and prolonged neointimal hyperplasia following endothelial denudation of carotid arteries
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• increase in neointimal formation and prolonged neointimal hyperplasia following endothelial denudation of carotid arteries
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• freshly isolated cells are more epithelioid shaped compared to the spindled shaped cells from control mice
• alpha-actin filaments are less abundant and often disrupted in quiescent smooth muscle cells
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• aortic smooth muscle cells challenged with PDGF-bb display more rapid alpha-actin filament disassembly and fillapodial extension and enhanced proliferation and migration compared to controls
• cultured aortic smooth muscle cells show enhanced serum induced cell growth
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• aortic rings mice fail to reach the 50% level of force generation at any concentration of KCl and phenylephrine tested
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• hypoxia-induced pulmonary hypertension is ameliorated in mutants
• hypoxia-induced increases in right ventricular systolic pressure, right ventricular end-diastolic pressure, peak rates of right ventricular pressure development and relaxation, right ventricle hypertrophy, pulmonary vascular remodeling, the number of CD45+ inflammatory cells in the hypoxic pulmonary artery, and pulmonary vascular cell proliferation are suppressed in mutants compared to controls
• however, mice show no differences in heart rate, systemic blood pressure, or left ventricular hemodynamic parameters before or after chronic hypoxia, no differences in pulmonary vasculature and right ventricular systolic pressure under normoxic conditions, and no differences in hemoglobin levels and platelet counts following long-term exposure to hypoxia compared to controls
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• in vitro, aortic vascular smooth muscle migration in response to fetal bovine serum is decreased
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• in vitro, aortic vascular smooth muscle cell proliferation in response to fetal bovine serum is decreased
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• levels of inflammatory cytokines like interferon-gamma and TNF-alpha secreted by vascular smooth muscle cells are reduced under both normoxic and hypoxic conditions
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• in vitro, aortic vascular smooth muscle migration in response to fetal bovine serum is decreased
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• in vitro, aortic vascular smooth muscle cell proliferation in response to fetal bovine serum is decreased
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• in vitro, aortic vascular smooth muscle cell proliferation in response to fetal bovine serum is decreased
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at 14 weeks of age, conscious mice show significantly higher mean blood pressure than control mice throughout the day, as measured by 24-hr radiotelemetry
• however, circadian variations in heart rate are not significantly altered
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• at 14 weeks of age, conscious mice show significantly higher diastolic blood pressure than control mice throughout the day, as measured by 24-hr radiotelemetry
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• under resting conditions, conscious mice exhibit significantly higher systolic blood pressure than control mice at 8 and 22 weeks of age, as measured by the tail-cuff method
• at 14 weeks of age, conscious mice show significantly higher systolic blood pressure than control mice throughout the day, as measured by 24-hr radiotelemetry
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• mutant femoral artery rings are hyperreactive to the maximum concentration of phenylephrine (10-5 M) relative to control rings (84.1% vs 54.4% KCl contraction, respectively)
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• mutant femoral artery rings are hyperreactive to the maximum concentration of phenylephrine (10-5 M) relative to control rings (84.1% vs 54.4% KCl contraction, respectively)
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• in primary culture, mutant aortic vascular smooth muscle cells (VSMCs) show higher intracellular calcium concentrations than control VSMCs both before (baseline) and after phenylephrine stimulation
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| N |
• mice exhibit normal body weight at 8-36 weeks of age
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die within 14 days of birth from cardiomyopathy and heart failure
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• at P8, cardiac mitochondria display an immature pattern with reduced cross-sectional area and intermitochondrial contacts relative to wild-type mitochondria
• however, mitochondrial DNA content is normal
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• lipid droplet accumulation in neonatal cardiomyocytes, unlike in wild-type hearts
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• increased heart weight to tibia length ratio relative to wild-type controls
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• progressive decrease in ejection fraction from P6 to P11
• M-mode echocardiograms revealed a decline in fractional shortening at P11
• however, no increase of apoptosis in P7 ventricles, as shown by TUNEL assays
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• pinacidil (a KATP channel opener) fails to produce a robust current increase in neonatal cardiomyocytes, unlike in wild-type controls
• mitochondria from neonatal cardiomyocytes are unresponsive to the KATP agonist diazoxide, consistent with with reduced or absent mitochondrial KATP activity
• rapid loss of mitochondrial membrane potential in isolated neonatal cardiomyocytes after exposure to hydrogen peroxide, indicating reduced resistance to cell stress relative to wild-type cardiomyocytes
• mitochondria show a reduced oxygen consumption rate, lack pinacidil responsiveness, and fail to increase oxygen consumption after FCCP treatment, unlike wild-type mitochondria
• failure to fuse and form larger mitochondria in neonatal cardiomyocytes from P2 to P8
• reduced fatty acid oxidation in neonatal cardiomyocytes after palmitate application
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• neonatal cardiomyopathy due to failure of the newborn myocardium to transition normally from fetal to mature (oxidative) metabolism
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| N |
• nonfasting serum glucose levels are normal at P5-P7
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• reduced fatty acid oxidation in neonatal cardiomyocytes after palmitate application
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• cardiac mitochondria show a reduced oxygen consumption rate, lack pinacidil responsiveness, and fail to increase oxygen consumption after treatment with FCCP (a mitochondrial uncoupling agent), unlike wild-type mitochondria
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• neonatal cardiomyocytes appear to be in a hypoxic state due to their inability to transition to fatty acid oxidation
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• at P8, cardiac mitochondria display an immature pattern with reduced cross-sectional area and intermitochondrial contacts relative to wild-type mitochondria
• however, mitochondrial DNA content is normal
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• failure to fuse and form larger mitochondria in neonatal cardiomyocytes from P2 to P8
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• neonatal cardiomyocytes are more susceptible to cell death in response to H2O2-induced stress relative to wild-type controls
• opening of KATP channels with pinacidil is less cardioprotective than in wild-type cardiomyocytes
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• mitochondria from neonatal cardiomyocytes are unresponsive to the KATP agonist diazoxide, consistent with with reduced or absent mitochondrial KATP activity
• rapid loss of mitochondrial membrane potential in isolated neonatal cardiomyocytes following cell stress induced by exposure to hydrogen peroxide, unlike in wild-type cardiomyocytes
• mitochondria show a reduced oxygen consumption rate, lack pinacidil responsiveness, and fail to increase oxygen consumption after treatment with FCCP (a mitochondrial uncoupling agent), unlike wild-type mitochondria
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• reduced fatty acid oxidation in neonatal cardiomyocytes after palmitate application
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• increased reactive oxygen species in isolated neonatal cardiomyocytes, as shown by increased dihydroethidium staining relative to wild-type controls
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• at P8, cardiac mitochondria display an immature pattern with reduced cross-sectional area and intermitochondrial contacts relative to wild-type mitochondria
• however, mitochondrial DNA content is normal
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• progressive decrease in ejection fraction from P6 to P11
• M-mode echocardiograms revealed a decline in fractional shortening at P11
• however, no increase of apoptosis in P7 ventricles, as shown by TUNEL assays
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• neonatal cardiomyopathy due to failure of the newborn myocardium to transition normally from fetal to mature (oxidative) metabolism
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• increased heart weight to tibia length ratio relative to wild-type controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• there is a 50% mortality rate between birth and weaning
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• pulmonary arteries of E18.5 embryos and newborns are significantly smaller
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• aorta diameters of all E18.5 embryos and newborns are decreased compared to wild-type mice
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• mean aortic velocity in one month old mice is 1.74 m/s which is significantly faster than the mean velocity of 0.93 m/s for controls
• mean pulmonary velocity in one month old mice is 1.9 m/s which is significantly faster than the mean velocity of 1.5 m/s for controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die between E12.5 and E16.5; only resorbed homozygous embryos are recovered at E16.5
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• while yolk sacs are normal at E9.5 by E12.5 yolk sacs are pale, anemic and possess obvious vasculature defects
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• at E12.5, yolk sacs are pale and anemic
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• while yolk sacs are normal at E9.5 by E12.5 yolk sacs are pale, anemic and possess obvious vasculature defects
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• mice exhibit delayed underdeveloped hearts
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• mice exhibit delayed underdeveloped brains
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• increased susceptibility to ischemic injury seen in Notch3 null mice is not rescued by expression of the mutant human NOTCH3 at 1 year of age but is rescued at 3 to 6 months of age
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• increased susceptibility to ischemic injury seen in Notch3 null mice is not rescued by expression of the mutant human NOTCH3 at 1 year of age but is rescued at 3 to 6 months of age
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| CADASIL 1 | DOID:0111035 |
OMIM:125310 |
J:171887 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Vascular smooth muscle cell abnormalities in Gt(ROSA)26Sortm3(NOTCH3*R1031C)Sat/Gt(ROSA)26Sor+ Tg(Tagln-cre)1Her/0 and Gt(ROSA)26Sortm2(NOTCH3*C455R)Sat/Gt(ROSA)26Sor+ Notch3Gt(PST033)Byg/Notch3Gt(PST033)Byg Tg(Tagln-cre)1Her/0 mice
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• vascular smooth muscle cell abnormalities with intracellular inclusions are seen at 6 months of age
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• increased susceptibility to ischemic injury seen in Notch3 null mice is not rescued by expression of the mutant human NOTCH3
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• vascular smooth muscle cell abnormalities with intracellular inclusions are seen at 6 months of age
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• increased susceptibility to ischemic injury seen in Notch3 null mice is not rescued by expression of the mutant human NOTCH3
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| CADASIL 1 | DOID:0111035 |
OMIM:125310 |
J:171887 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• increased susceptibility to ischemic injury seen in Notch3 null mice is rescued by expression of the human NOTCH3
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• hyperproliferation and disarray of aorta smooth muscle cells at 3 months of age
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• the medium of the aortic wall is thicker than in single Agtr2 mutants, with hyperproliferation and disarray of smooth muscle cells at 3 months of age
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• mice develop aneurysms
• treatment with losartan completely prevents aneurysms
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• hyperproliferation and disarray of aorta smooth muscle cells at 3 months of age
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| aortic aneurysm | DOID:3627 | J:213282 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• following filament middle cerebral artery occlusion, mice exhibit reduced infarct volume compared with similarly treated Notch3Gt(PST033)Byg homozygotes
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• following filament middle cerebral artery occlusion, mice exhibit reduced infarct volume compared with similarly treated Notch3Gt(PST033)Byg homozygotes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• aortic wall is thicker at 3 months of age compared to single Agtr1a homozygotes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice exposed to increasing doses of thromboxane receptor agonist U-46619 exhibit an attenuated dose-dependent increase in airway resistance unlike control mice
• mice exposed to U-46619 and methacholine exhibit less of an increased in airway resistance compared with control mice
• however, mice exposed ovalbumin and U-46619 exhibit dose-dependent increase in airway resistance
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mild dilation of the heart
• no cardiomyopathy, cardiac hypertrophy, or differences in heart rate and have normal blood vessel development, blood vessel morphology in adults, angiogenesis and vascular remodeling response
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• at 9 months of age, females, but not males, show larger systolic and diastolic LV internal diameters and decreased fractional shortening, indicating decreased cardiac contractility
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• females, but not males, perform worse in a treadmill experiment
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• at 9 months of age, females, but not males, show larger systolic and diastolic LV internal diameters and decreased fractional shortening, indicating decreased cardiac contractility
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• females, but not males, perform worse in a treadmill experiment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Massive hemorrhage in Prdm6tm1.1Jrld/Prdm6tm1.2Jrld; Tg(Tagln-cre)1Her lungs
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• newborn mice die within 2 days after birth
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• newborn mice die within 2 days after birth
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• massive
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• massive
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• dilated and dysmorphic vessels in brains of 5 week old mice
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• 90% of 5 week old mice exhibit arteriovenous malformations with greatly enlarged and tortuous vessels in the brain
• more than 80% of mice have one arteriovenous malformation lesion, while the remaining 20% have 2-3 lesions
• arteriovenous (A-V) shunting and hemorrhage are seen in some brain and spinal cord lesions
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• arteriovenous malformations are also seen in the spinal cord and intestine
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• hemorrhage is seen in some brain and spinal cord lesions
• macrophages and microhemorrhage are seen around dysplastic vessels in the brain
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• arteriovenous malformations are also seen in the spinal cord and intestine
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• more than 50% of mice before 6 weeks of age
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hereditary hemorrhagic telangiectasia | DOID:1270 |
OMIM:187300 OMIM:600376 OMIM:601101 OMIM:615506 |
J:212952 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at P0, the aortic laminae is disrupted unlike in wild-type mice
• at P14, the elastic laminae is disrupted unlike in wild-type mice
• at 12 weeks, aorta are less distensible than in wild-type mice
• mice loss the internal elastic lamina in the ascending aorta unlike wild-type mice
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• slightly elongated
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• severe ascending aortic aneurysms
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• the ascending aorta from the aortic root to just distal to the branching point of the brachiocephalic artery is dilated
• however, no aortic stenosis is observed
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• at 12 weeks, aorta are less distensible and stiffer than in wild-type mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• following wire injury, mice exhibit accelerated intimal hyperplasia with increased intima to media ratio and stenosis percent compared with control mice
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• decreased IL1beta-stimulated prostaglandin E2
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• increased IL1beta-stimulated prostaglandin D2 and I2 levels
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| N |
• whether fed standard chow or a high salt diet, mice exhibit normal modulation of blood pressure and thrombogenesis
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• following wire injury, mice exhibit accelerated intimal hyperplasia with increased intima to media ratio and stenosis percent compared with control mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• unlike hypertensive homozygous null mice, conscious conditional mutants exhibit normal chronic arterial BPs under resting conditions, despite abolition of vasorelaxing responses to ANP
• however, infusion of ANP at a dose of 500 ng/kg BW fails to lower arterial BP in conscious conditional mutants but significantly reduces systolic and diastolic BP in wild-type and homozygous Npr1tm1Kuhn mice
• notably, acute vascular volume expansion results in a rapid, significant increase in systolic BP and slight increase in diastolic BP during the 15 min of high-volume infusion; such changes are fully reversible 10 min after volume overload and are absent in homozygous Npr1tm1Kuhn mice
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• vasorelaxing responses to atrial natriuretic peptide (ANP) are abolished in isolated preconstricted arteries from conditional mutant mice
• small relaxation in response to high ANP concentrations, also observed in phenylephrine (PE)-contracted arteries in the absence of ANP, indicating a spontaneous (ANP-independent) loss of tone
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• vasorelaxing responses to atrial natriuretic peptide (ANP) are abolished in isolated preconstricted arteries from conditional mutant mice
• small relaxation in response to high ANP concentrations, also observed in phenylephrine (PE)-contracted arteries in the absence of ANP, indicating a spontaneous (ANP-independent) loss of tone
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice exhibit increased meal duration with reduced rate of food intake compared with control mice
• however, meal size is normal
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 50% of mutants die by P1
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• no mutants survive past P2
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• seen in some mutants
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• 95% of mutants exhibit patent ductus arteriosus
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• defects in vascular smooth muscle cell differentiation in the outer layers of the medial wall of the ductus arteriosus and descending aorta at E17.5 when the ductus arteriosus is still patent, however the ascending limb of the aorta and the pulmonary artery trunk have normal vascular smooth muscle cell differentiation
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• defects in vascular smooth muscle cell differentiation in the outer layers of the medial wall of the ductus arteriosus and descending aorta at E17.5 when the ductus arteriosus is still patent, however the ascending limb of the aorta and the pulmonary artery trunk have normal vascular smooth muscle cell differentiation
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• 95% of mutants exhibit patent ductus arteriosus
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit increased meal duration with reduced rate of food intake compared with control mice
• mice exhibit a satiation deficit compared with control mice
• however, mice exhibit normal meal size and oropharyngeal-positive feedback signaling
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• mice exhibit reduced solitary tract nucleus and area postrema meal-induced c-Fos activation, suggesting a decrease in vagal afferent signaling, compared with control mice
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| N |
• mice exhibit normal body weight
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Vascular smooth muscle cell abnormalities in Gt(ROSA)26Sortm3(NOTCH3*R1031C)Sat/Gt(ROSA)26Sor+ Tg(Tagln-cre)1Her/0 and Gt(ROSA)26Sortm2(NOTCH3*C455R)Sat/Gt(ROSA)26Sor+ Notch3Gt(PST033)Byg/Notch3Gt(PST033)Byg Tg(Tagln-cre)1Her/0 mice
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• thinning of the vascular smooth muscle layers
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• osmiophilic granular deposits in mice older than 12 months of age
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• vascular smooth muscle cell abnormalities with intracellular inclusions and lipid droplets that get more severe with age
• thinning of the vascular smooth muscle layers
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• vascular smooth muscle cell abnormalities with intracellular inclusions and lipid droplets that get more severe with age
• thinning of the vascular smooth muscle layers
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• osmiophilic granular deposits in mice older than 12 months of age
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| CADASIL 1 | DOID:0111035 |
OMIM:125310 |
J:171887 | |
|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased muscularization of pulmonary arteries at the alveolar wall
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• elevated right ventricular systolic pressure
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| primary pulmonary hypertension | DOID:14557 |
OMIM:178600 OMIM:265400 OMIM:615342 OMIM:615343 OMIM:615344 |
J:136168 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal survival
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• mice exhibit alterations in the ascending aorta at 2 weeks that progresses through the arch and descending aorta to affect the entire thoracic and abdominal aorta by 4 weeks unlike in wild-type mice
• mice exhibit reduced periaortic adipose compared to in wild-type mice
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• thickened
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• authors state that mice exhibit the aorta phenotype observed in mice expressing the floxed allele and Tg(Sox2-cre)1Amc
• however, aorta histology is normal in neonates
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• by 4 weeks
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• by 4 weeks
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• by 4 weeks
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• by 4 weeks
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• increased radius
• 2-fold dilation that reaches homeostasis without rupture or apoptosis of vascular smooth muscle cells
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• at P7, retinal capillary size is increased compared to in wild-type mice
• at P12, brain capillary size is increased compared to in wild-type mice
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• reduced vessel density
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• reduced vessel density
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• pericyte coverage of brain and retinal vasculature is increased compared to in wild-type mice
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• mice exhibit increased vascular smooth muscle cell cellularity within the aorta compared with wild-type mice
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• at E18.5, mice exhibit increased vascular smooth muscle cell (VSMC) proliferation in the aorta compared with wild-type mice
• cultured aorta release >4-fold more VSMCs due to increased proliferation compared with wild-type cultures
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• mice exhibit reduced periaortic adipose compared to in wild-type mice
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| N |
• mice exhibit normal growth
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• mice exhibit increased vascular smooth muscle cell cellularity within the aorta compared with wild-type mice
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• at E18.5, mice exhibit increased vascular smooth muscle cell (VSMC) proliferation in the aorta compared with wild-type mice
• cultured aorta release >4-fold more VSMCs due to increased proliferation compared with wild-type cultures
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• reduced vessel density
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• reduced vessel density
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• at E18.5, mice exhibit increased vascular smooth muscle cell (VSMC) proliferation in the aorta compared with wild-type mice
• cultured aorta release >4-fold more VSMCs due to increased proliferation compared with wild-type cultures
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice display partial perinatal lethality
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• VSDs are observed
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• contractile dysfunction observed
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• contractile dysfunction observed
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die at 2 months of age
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• increase in proliferation of aorta vessel wall at 1 month of age
• vessel area is increased in the aorta
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• increased in thickness
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• disorganized
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• smooth muscle cells of the aorta are abnormal by P14 and their proliferation extends throughout the medial layer
• hyperproliferation and disarray of smooth muscle cells in the ascending aorta wall at 3 months of age
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• focal lesions with thickened aortic wall
(J:170883)
• increased collagen fibers
(J:170883)
• cellularity in the aorta is increased by P7, especially in the subendothelial layer and near the adventitia
(J:213282)
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• captopril, an ACE inhibitor, or losartan treatment of pregnant females and continued until 3 months of age, completely prevents aneurysm formation and hyperproliferaton and disarray of smooth muscle cells in the aortic wall, however amount of collagen is decreased, and elastic fibers remain irregular
(J:213282)
• administration of losartan starting at P7 completely prevents aneurysms, however administration from P30 to P90 does not prevent aneurysms
(J:213282)
• however, propranolol, a beta-adrenergic receptor blocker, treatment shows modest inhibitory effects on aneurysm formation
(J:213282)
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• slight dilatation of the ascending aorta is seen at P14
|
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• vascular smooth muscle cells exhibit defective differentiation compared to in wild-type mice
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• pulse pressures are increased 50%
• captopril treatment decreases this increase in pulse pressure
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• mice show a trend toward lower average diastolic pressures
• captopril treatment decreases systolic blood pressures about 20% in mutants, however losartan or propranolol have no effect on blood pressure
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• compliance of the ascending aorta is decreased 60-80% in the middle-to high-pressure range (75-175 mmHg), indicating that the vessel wall is stiffer
• treatment with losartan or captopril does not completely reverse the increase in vessel wall stiffness
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• vascular smooth muscle cells exhibit defective differentiation compared to in wild-type mice
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• smooth muscle cells of the aorta are abnormal by P14 and their proliferation extends throughout the medial layer
• hyperproliferation and disarray of smooth muscle cells in the ascending aorta wall at 3 months of age
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| aortic aneurysm | DOID:3627 | J:213282 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice are grossly normal and display normal coronary endothelial patterning at E12.5; mice live to adulthood and are indistinguishable from wild-type littermates
|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• amyloid beta deposition in the brains is higher than in controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 13-14 months of age
• amyloid beta deposition is seen in the cortical parenchyma and in cortical vessels as cerebral amyloid angiopathy
• concentrations of insoluble amyloid beta40 and amyloid beta42 is higher than in controls at 13-14 months of age but not at 3 months
• despite the increase in amyloid beta deposition, APP processing and levels of amyloid beta degrading enzymes are normal, indicating that the increase is due to a disturbance of lysosomal-mediated amyloid beta clearance
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• amyloid beta deposition is seen in cortical vessels as cerebral amyloid angiopathy
|
|
• activation of astrocytes is enhanced compared to controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 1 year of age
|
|
• amyloid beta deposition in the brains is higher than in controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 13-14 months of age
• amyloid beta deposition is seen in the cortical parenchyma and in cortical vessels as cerebral amyloid angiopathy
• concentrations of insoluble amyloid beta40 and amyloid beta42 is higher than in controls at 13-14 months of age but not at 3 months
• despite the increase in amyloid beta deposition, APP processing and levels of amyloid beta degrading enzymes are normal, indicating that the increase is due to a disturbance of lysosomal-mediated amyloid beta clearance
|
|
• amyloid beta deposition is seen in cortical vessels as cerebral amyloid angiopathy
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Alzheimer's disease | DOID:10652 | J:192453 | ||
| cerebral amyloid angiopathy | DOID:9246 | J:192453 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal testis position
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice fed a high-fat diet exhibit the same amount of angiotensin-induced expansion of ascending aortas and aneurysms as in similarly treated Ldlrtm1Her homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• grossly disrupted
|
|
• progressive thickening of the aorta wall with age
• thickening is primarily caused by increased smooth muscle cell proliferation
|
|
• aortas are consistently distended and dilated
|
|
• pronounced atherosclerosis is seen in the aorta
|
|
• on a high cholesterol diet
• addition of Gleevec to the diet protects against atherosclerotic lesion formation
|
|
• almost complete occlusion of the mesenteric arteries
|
|
• increase in vascular smooth muscle cell proliferation
|
|
• increase in vascular smooth muscle cell proliferation
|
| N |
• no changes in cholesterol or triglyceride levels are detected compared to mice homozygous for Ldlrtm1Her alone
|
|
• increase in vascular smooth muscle cell proliferation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• ascending aortas are characterized by increased cell nuclei and fractured elastic laminae and show progressive intra-lamellar thickening, extracellular matrix deposition, and cellular disorganization
• medial layers of the ascending aorta exhibits increased cellular and intracellular accumulation of connective tissue growth factor
|
|
• dilated ascending aortas in mice older than 36 weeks of age
|
|
• dilation of aortic roots is seen beginning at 16 weeks of age and progresses with age
|
|
• coronary arteries within the left ventricle show accumulation of collagen within the tunica media and adventitia
|
|
• increase in perivascular fibrosis with outward extension of fibrotic lesions surrounding intramural coronary arteries in 48 week old mice
• extensive and continuous fibrotic lesions tracts extending outward from coronary arteries are sporadically seen in ventricle walls
|
|
• increase in myocyte longitudinal area in parenchymal regions of the left ventricle free wall in 48 week old mice
|
|
• increase in heart size in mice older than 36 weeks of age
|
|
• heart weight to body weight ratios are increased throughout the age range from 16 to 70 weeks of age
|
|
• left ventricle enlargement in 48 week old mice
|
|
• interstitial fibrosis in intramural coronary arteries of left ventricle free wall and extensive fibrosis in left ventricle papillary muscles
• however, no pericellular fibrosis is seen
|
|
• a 38% reduction in fractional shortening and 43% reduction in ejection fraction
|
|
• echocardiography shows a reduction in systolic function, with a 38% reduction in fractional shortening, 43% reduction in ejection fraction, and 68% increase in left ventricular diameter in 36 week old mice
|
|
• mice show age-dependent increase in incidence of aortic insufficiency, with all mice showing it at 30 weeks of age
|
|
• 24 week old mice exhibit a 44% higher pulse pressure than controls
• captopril treatment reduces pulse pressure to levels seen in untreated control mice
|
|
• 16% reduction in diastolic pressure in 24 week old mice
• however, systolic blood pressure is normal
|
|
• increase in myocyte longitudinal area in parenchymal regions of the left ventricle free wall in 48 week old mice
|
|
• a 38% reduction in fractional shortening and 43% reduction in ejection fraction
|
|
• increase in heart size in mice older than 36 weeks of age
|
|
• heart weight to body weight ratios are increased throughout the age range from 16 to 70 weeks of age
|
|
• interstitial fibrosis in intramural coronary arteries of left ventricle free wall and extensive fibrosis in left ventricle papillary muscles
• however, no pericellular fibrosis is seen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| cardiomyopathy | DOID:0050700 | J:209752 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• time of lethality not specified
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal basal cardiac and vascular function
|
|
• slight at 8 months of age
|
|
• mild at 8 months of age
|
|
• mice fail to develop ACTH- or ouabain-induced hypertension unlike similarly treated wild-type mice
• however, basal systemic blood pressure is normal
|
|
• slight at 8 months of age
|
|
• mild at 8 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 34.6% of mice die suddenly by 1 year of age
|
|
• some sudden death of several pups before weaning at 4 weeks of age is seen
|
|
• aortas are thinner
|
|
• widening of the gaps at the intercalated discs in the myocardium of 25 week old mice
• desmosomes are less electron-dense than in controls at 25 weeks of age and the gap width at the desmosomes is increased
• distribution of desmosomal proteins is altered
|
|
• right ventricle shows disorganized myocardial structure with poorly defined cell junctional areas
|
|
• massive fat accumulation in the right ventricle free wall adjacent to areas of fibrosis is seen in 19 week old mice
|
|
• heart weight to body weight ratio is increased
|
|
• ventricular weight to body weight ratio is increased
|
|
• thinning of interventricular septum of the hearts of E12.5 and E14.5 embryos
|
|
• massive fat accumulation in the right ventricle free wall adjacent to areas of fibrosis is seen in 19 week old mice
|
|
• thinning of ventricular walls of the hearts of E12.5 and E14.5 embryos
|
|
• myocardial fibrotic changes are first evident at P3 in both the right and left ventricles
• fibrosis is initially seen in epicardial and perivascular regions of the ventricles, progressing to adjacent myocardium with age and involving the entire thickness of the right ventricle free wall at 19 weeks of age
|
|
• hearts are markedly dilated as early as P3, with dilatation more prominent in the right ventricle and is progressive with age
|
|
• progressive ventricular dilatation and thinning from P3
|
|
• reduction in left ventricle ejection fraction and fractional shortening
|
|
• reduction in the number of proliferating cardiomyocytes in the ventricular walls and interventricular septum (both in compact layer and trabeculated layer) in E12.5 hearts
• however, apoptosis levels are normal
|
|
• echocardiography indicates dilated ventricular chambers, increased right ventricle and left ventricle dimensions, and reduced left ventricle ejection fraction and fractional shortening
|
|
• mice frequently exhibit spontaneous ventricular arrhythmias, evident as long frequent runs of ventricular extrasystoles characterized by widened QRS complexes with no apparent association with the P waves
|
|
• reduction in the number of proliferating cardiomyocytes in the ventricular walls and interventricular septum (both in compact layer and trabeculated layer) in adult hearts
|
|
• systolic blood pressure is lower
|
|
• mice develop arrhythmogenic right ventricular cardiomyopathy
|
|
• reduction in the number of proliferating cardiomyocytes in the ventricular walls and interventricular septum (both in compact layer and trabeculated layer) in E12.5 hearts
• however, apoptosis levels are normal
|
|
• widening of the gaps at the intercalated discs in the myocardium of 25 week old mice
• desmosomes are less electron-dense than in controls at 25 weeks of age and the gap width at the desmosomes is increased
• distribution of desmosomal proteins is altered
|
|
• right ventricle shows disorganized myocardial structure with poorly defined cell junctional areas
|
|
• massive fat accumulation in the right ventricle free wall adjacent to areas of fibrosis is seen in 19 week old mice
|
|
• reduction in left ventricle ejection fraction and fractional shortening
|
|
• reduction in the number of proliferating cardiomyocytes in the ventricular walls and interventricular septum (both in compact layer and trabeculated layer) in E12.5 hearts
• however, apoptosis levels are normal
|
|
• mice develop arrhythmogenic right ventricular cardiomyopathy
|
|
• heart weight to body weight ratio is increased
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| arrhythmogenic right ventricular cardiomyopathy | DOID:0050431 |
OMIM:PS107970 |
J:242116 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal aortic structure
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal blood pressure and vasodilatory response to acetylcholine
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at P14, the elastic laminae is disrupted unlike in wild-type mice
• at 12 weeks, aorta are less distensible than in wild-type mice
• the elastic laminae is thicker and spongy with aberrant deposits in the interlaminar spaces unlike in wild-type mice
|
|
• at 12 weeks, aorta are less distensible and stiffer than in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• treatment with angiotensin II to induce hypertension induced mortality in 32.3% of mice, similar treatment induced no deaths in controls
|
|
• some die suddenly at 8 weeks of age
• gradual increase in mortality with age with 13 of 30 mice dying before 72 weeks of age
• treatment with ponatinib, which inhibits MEKK3 and MEKK2 signaling, increases survival rates
|
|
• false lumen formation, intramural hematomas and dissections at 8 weeks of age
• media thickness, disorganization, and decreased expression of cyto-skeletal protein are seen before and after angiotensin II treatment
|
|
• decreased thickness
|
|
• disruption and degradation of collagen and medial elastic lamina
|
|
• decreased medial thickness and degradation of the aortic wall
|
|
• marked increase in diameter of the abdominal aorta at 8 weeks of age
|
|
• marked increase in diameter at 8 weeks of age
|
|
• incidence increases with age
• develop aortic hematoma or dissection at 8 weeks of age
• at 24 weeks of age, aortic rupture across the intima and media, dissection of the aortic wall with blood collection between the media and fragmentation the elastic layers are seen
• about 63% of mice receiving angiotensin II develop serious dissections in the aorta arch and abdominal aorta, dissections do not develop in similarly treated controls
|
|
• dilated aneurysms in the thoracic and abdominal aorta from 24 weeks of age
|
|
• from 24 weeks of age
|
|
• from 24 weeks of age
|
|
• mice die of massive hemorrhage in the thoracic or peritoneal cavity
|
|
• increased apoptosis of vascular smooth muscle cells in the aorta
|
|
• increased numbers of CD68-positive macrophages in the aorta indicating involvement of inflammation in the development of aortic dissection
|
|
• increased numbers of CD68-positive macrophages in the aorta indicating involvement of inflammation in the development of aortic dissection
|
|
• increased apoptosis of vascular smooth muscle cells in the aorta
|
|
• increased apoptosis of vascular smooth muscle cells in the aorta
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| aortic dissection | DOID:0080685 | J:338981 | ||
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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 04/16/2024 MGI 6.23 |
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