Phenotypes Associated with This Genotype

Genotype
MGI:4429555

• Allelic Composition: Tg(Notch3*R169C)88Bbb/0
• Genetic Background: involves: FVB/N

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

Tg(Notch3*R169C)88Bbb/0 mice exhibit granular osmiophilic material deposits in smooth muscle cells

cardiovascular system

abnormal capillary morphology ( J:156682 )

• by 12 months, capillaries in the corpus callosum exhibit reduced length compared to in wild-type mice

abnormal brain vasculature morphology ( J:156682 )

• at 5 months, pial arteries contain granular osmiophilic material (GOM) and Notch3 extracellular domain aggregates unlike in wild-type mice

• by 10 to 12 months, GOM deposits increase with age and are widely distributed compared to in wild-type mice

• passive internal diameter of cerebral arteries after deactivation of smooth muscle cells is less than in wild-type mice

• the difference between active and passive diameter (dilator reserve) is reduced compared to in wild-type mice

• however, cerebral artery wall thickness is normal

abnormal cerebral artery morphology ( J:220006 )

• about 60% increase in the number of voltage-gated potassium (Kv1) channels in cerebral smooth muscle cells

abnormal blood flow velocity ( J:156682 )

• 18 to 20 months, mice exhibit decreased resting cerebral blood flow in the cortex, forebrain, and thalamus compared with wild-type mice

abnormal blood vessel physiology ( J:156682 )

• mice exhibit impaired adaptive responses of cerebral circulation during changes in arterial pressure unlike in wild-type mice

• the lower limit of cortical blood flow auto-regulation is shifted to a higher blood pressure compared to in wild-type mice

• phenylephrine-induced acute hypertension induces less of an increase in cortical blood flow compared to in similarly treated wild-type mice

• however, mice exhibit normal resting arterial blood pressure, hypercapnia-induced vasodilation, and blood-brain barrier

• cerebral blood flow elicited by whisker stimulation is attenuated compared to in wild-type mice

• pressure-induced contraction of arteries is attenuated compared to in wild-type mice

abnormal vascular smooth muscle physiology ( J:220006 )

• voltage-gated potassium channel current density is increased in cerebral artery myocytes

• inhibition of voltage-gated potassium channels with 4-aminopyridine or treatment with the epidermal growth factor receptor agonist heparin-binding EGF reduces Kv current density

decreased vasoconstriction ( J:156682 , J:220006 )

• myogenic tone of cerebral arteries is decreased compared to in wild-type mice (J:156682)

• brain parenchymal arterioles and posterior cerebral arteries show blunted constriction to pressure (myogenic tone) at physiological pressure of 40 mm Hg at 6 months of age (J:220006)

• blunted myogenic tone is due to smooth muscle membrane potential hyperpolarization (J:220006)

• inhibition of voltage-gated potassium channels with 4-aminopyridine or treatment with the epidermal growth factor receptor agonist heparin-binding EGF restores myogenic responses to parenchymal arterioles (J:220006)

nervous system

abnormal brain vasculature morphology ( J:156682 )

• at 5 months, pial arteries contain granular osmiophilic material (GOM) and Notch3 extracellular domain aggregates unlike in wild-type mice

• by 10 to 12 months, GOM deposits increase with age and are widely distributed compared to in wild-type mice

• passive internal diameter of cerebral arteries after deactivation of smooth muscle cells is less than in wild-type mice

• the difference between active and passive diameter (dilator reserve) is reduced compared to in wild-type mice

• however, cerebral artery wall thickness is normal

abnormal cerebral artery morphology ( J:220006 )

• about 60% increase in the number of voltage-gated potassium (Kv1) channels in cerebral smooth muscle cells

abnormal brain white matter morphology ( J:156682 )

• at 18 to 20 months, mice exhibit extensive cerebral white matter damage unlike in wild-type mice

• mice exhibit white matter degeneration unlike in wild-type mice

brain vacuoles ( J:156682 )

• at 18 to 20 months in the white matter

astrocytosis ( J:156682 )

• at 20 months

abnormal myelination ( J:156682 )

• at 18 to 20 months, mice exhibit loss of compact myelin with disorganized fibers unlike in wild-type mice

homeostasis/metabolism

decreased physiological sensitivity to xenobiotic ( J:156682 )

• phenylephrine-induced acute hypertension induces less of an increase in cortical blood flow compared to in similarly treated wild-type mice

muscle

abnormal vascular smooth muscle physiology ( J:220006 )

• voltage-gated potassium channel current density is increased in cerebral artery myocytes

• inhibition of voltage-gated potassium channels with 4-aminopyridine or treatment with the epidermal growth factor receptor agonist heparin-binding EGF reduces Kv current density

decreased vasoconstriction ( J:156682 , J:220006 )

• myogenic tone of cerebral arteries is decreased compared to in wild-type mice (J:156682)

• brain parenchymal arterioles and posterior cerebral arteries show blunted constriction to pressure (myogenic tone) at physiological pressure of 40 mm Hg at 6 months of age (J:220006)

• blunted myogenic tone is due to smooth muscle membrane potential hyperpolarization (J:220006)

• inhibition of voltage-gated potassium channels with 4-aminopyridine or treatment with the epidermal growth factor receptor agonist heparin-binding EGF restores myogenic responses to parenchymal arterioles (J:220006)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
brain ischemia		DOID:2316		J:156682
CADASIL 1		DOID:0111035	OMIM:125310	J:220006