Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries.
CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3R169Cmouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels, as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169Cmice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred before myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3R169Cmice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3R170C/R170C) exhibited similar reductions in arterial lumen, and both TgNotch3R169Cand Notch3R170C/R170Cmice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169Cmice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow.
From the Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, UMRS 1161, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); DHU NeuroVasc Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); and Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Celine
C
Baron-Menguy
From the Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, UMRS 1161, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); DHU NeuroVasc Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); and Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Valérie
V
Domenga-Denier
From the Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, UMRS 1161, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); DHU NeuroVasc Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); and Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Lamia
L
Ghezali
From the Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, UMRS 1161, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); DHU NeuroVasc Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); and Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Frank M
FM
Faraci
From the Genetics and Pathogenesis of Cerebrovascular Diseases, INSERM, UMRS 1161, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); DHU NeuroVasc Sorbonne Paris Cité, Paris, France (C.B.-M., V.D.-D., L.G., A.J.); and Departments of Internal Medicine and Pharmacology, Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.). anne.joutel@inserm.fr.
Anne
A
Joutel
D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D000071656:Receptor, Notch3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation
C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D004247:DNA
CADASIL; Notch3 protein, mouse; cerebral small vessel diseases; stroke; vasodilation