Published online before print April 7, 2005, doi: 10.1161/01.STR.0000163080.82766.eb
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(Stroke. 2005;36:1053.)
© 2005 American Heart Association, Inc.
Original Contributions |
Impaired Cerebral Vasoreactivity in a Transgenic Mouse Model of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Arteriopathy
From the Génétique des Maladies Vasculaires, INSERM U740, Faculté de Médecine Lariboisière-Saint Louis, Paris, France.
Correspondence to Pierre Lacombe, Génétique des Maladies Vasculaires, INSERM U740, Faculté de Médecine Lariboisière-Saint Louis, 10, Avenue de Verdun, 75010 Paris, France. E-mail lacombe{at}ext.jussieu.fr
Background and Purpose— Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The disease is caused by highly stereotyped mutations in NOTCH3, which is restrictively expressed in vascular smooth muscle cells (VSMCs). The mechanisms of compromised cerebral hemodynamics in CADASIL remain to be elucidated. We tested the hypothesis that mutant NOTCH3 impairs the vasomotor function of cerebral vessels.
Methods— Vasomotor function was examined in vivo in transgenic mice expressing a mutant NOTCH3 in VSMCs (TgNotch3R90C). Mice develop an age-dependent arteriopathy similar to that seen in CADASIL, without brain parenchyma lesions. Using laser-Doppler flowmetry, we assessed in awake TgNotch3R90C mice and wild-type littermates the cerebrovascular reactivity to 2 potent vasodilator stimuli (acetazolamide and hypercapnia) and cerebral blood flow (CBF) autoregulation during stepwise blood pressure elevations and reductions. Mice were studied at 18 months of age, when the CADASIL features are apparent, and at 10 months of age, before their appearance.
Results— Eighteen-month-old TgNotch3R90C mice showed reduced responses to hypercapnia and acetazolamide, higher cerebrovascular resistance during hypertension, and their lower limit of CBF autoregulation was shifted to higher blood pressures. Cerebrovascular responses were similarly impaired in 10-month-old TgNotch3R90C mice.
Conclusions— Cerebrovascular reactivity is compromised early in TgNotch3R90C mice. The data show an impaired autoregulation and are suggestive of a decreased relaxation or increased resistance of cerebral vessels. Our findings indicate that vascular dysfunction is an early pathogenic event that may promote the subsequent development of brain ischemia in CADASIL.
Key Words: autoregulation • CADASIL • laser-Doppler flowmetry
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