Published Online
on November 29, 2004

A more recent version of this article appeared on January 1, 2005

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Submitted on September 3, 2004
Revised on October 18, 2004
Accepted on October 19, 2004

Impaired Vascular Mechanotransduction in a Transgenic Mouse Model of CADASIL Arteriopathy

Caroline Dubroca MSc; Pierre Lacombe PhD; Valérie Domenga; Jacqueline Maciazek; Bernard Levy MD, PhD; Elisabeth Tournier-Lasserve MD; Anne Joutel MD, PhD^*; and Daniel Henrion PharmD, PhD

From INSERM U541 (C.D., B.L.), Université Paris 7, Paris, France; INSERM E365 (V.D., P.L., J.M., E.T.L., A.J.), Paris, France; the Laboratoire de Cytogénétique (E.T.L., A.J.), Hôpital Lariboisière, Paris, France; and CNRS-UMR 6188 (D.H.), Université d’Angers, Angers, France.

^* To whom correspondence should be addressed. E-mail: joutel{at}paris7.jussieu.fr.

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.

Key words: CADASIL • cognitive disorders • lacunar infarction • mice, transgenic

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