Search

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.

Background and Purpose: CADASIL is an inherited small-vessel disease responsible for lacunar strokes and cognitive impairment. The disease is caused by highly stereotyped mutations in Notch3, the expression of which is highly restricted to vascular smooth muscle cells (VSMCs). The underlying vasculopathy is characterized by degeneration of VSMCs and the accumulation of granular osmiophilic material (GOM) and Notch3 protein within the cell surface of these cells. In this study, we assessed early functional changes related to the expression of mutant Notch3 in resistance arteries., Methods: Vasomotor function was examined in vitro in arteries from transgenic mice that express a mutant Notch3 in VSMC. Tail artery segments from transgenic and normal wild-type male mice were mounted on small-vessel arteriographs, and reactivity to mechanical (flow and pressure) forces and pharmacological stimuli were determined. Mice were studied at 10 to 11 months of age when VSMC degeneration, GOM deposits, and Notch3 accumulation were not yet present., Results: Passive arterial diameter, contraction to phenylephrine, and endothelium-dependent relaxation to acetylcholine were unaffected in transgenic mice. By contrast, flow-induced dilation was significantly decreased and pressure-induced myogenic tone significantly increased in arteries from transgenic mice compared with wild-type mice., Conclusions: This is the first study to our knowledge providing evidence that mutant Notch3 impairs selectively the response of resistance arteries to flow and pressure. The data suggest an early role of vascular dysfunction in the pathogenic process of the disease.

Formation of a fully functional artery proceeds through a multistep process. Here we show that Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC). In adult Notch3-/- mice distal arteries exhibit structural defects and arterial myogenic responses are defective. The postnatal maturation stage of vSMC is deficient in Notch3-/- mice. We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells. Our data reveal Notch3 to be the first cell-autonomous regulator of arterial differentiation and maturation of vSMC.