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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2216.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Notch3 Is a Major Regulator of Vascular Tone in Cerebral and Tail Resistance Arteries

E.J. Belin de Chantemèle; K. Retailleau; F. Pinaud; E. Vessières; A. Bocquet; A.L. Guihot; B. Lemaire; V. Domenga; C. Baufreton; L. Loufrani; A. Joutel; D. Henrion

From INSERM U771 (E.J.B.d.C., K.R., E.V., A.B., A.L.G., L.L., D.H.), Angers; CNRS UMR 6214 (E.J.B.d.C., K.R., E.V., A.B., A.L.G., L.L., D.H.), Angers; Université d’Angers (E.J.B.d.C., K.R., E.V., A.B., A.L.G., L.L., D.H.), Angers; CHU d’Angers (F.P., C.B., D.H.), Angers; INSERM U740 (B.L., V.D., A.J.), Paris; Université Paris 7 - Denis Diderot (B.L., V.D., A.J.), Faculté de Médecine, Site Lariboisière, Paris; and AP-HP, Groupe hospitalier LARIBOISIERE-FERNAND-WIDAL (A.J.), Groupement hospitalier-universitaire Nord, Laboratoire de Génétique, Paris, France.

Correspondence to Daniel Henrion, PharmD, PhD, INSERM U 771, CNRS UMR 6214, Faculté de Médecine, 49045 Angers, France. E-mail daniel.henrion{at}univ-angers.fr

Objective— Notch3, a member of the evolutionary conserved Notch receptor family, is primarily expressed in vascular smooth muscle cells. Genetic studies in human and mice revealed a critical role for Notch3 in the structural integrity of distal resistance arteries by regulating arterial differentiation and postnatal maturation.

Methods and Results— We investigated the role of Notch3 in vascular tone in small resistance vessels (tail and cerebral arteries) and large (carotid) arteries isolated from Notch3-deficient mice using arteriography. Passive diameter and compliance were unaltered in mutant arteries. Similarly, contractions to phenylephrine, KCl, angiotensin II, and thromboxane A2 as well as dilation to acetylcholine or sodium nitroprusside were unaffected. However, Notch3 deficiency induced a dramatic reduction in pressure-induced myogenic tone associated with a higher flow (shear stress)-mediated dilation in tail and cerebral resistance arteries only. Furthermore, RhoA activity and myosin light chain phosphorylation, measured in pressurized tail arteries, were significantly reduced in Notch3KO mice. Additionally, myogenic tone inhibition by the Rho kinase inhibitor Y27632 was attenuated in mutant tail arteries.

Conclusions— Notch3 plays an important role in the control of vascular mechano-transduction, by modulating the RhoA/Rho kinase pathway, with opposite effects on myogenic tone and flow-mediated dilation in the resistance circulation.

Notch3 regulates arterial differentiation and postnatal maturation of smooth muscle cells. By using arteries from Notch3 knockout mice we found that Notch3 plays an important role in the control of resistance arteries mechano-transduction, by modulating the RhoA/Rho kinase pathway, which is involved in pressure-induced (myogenic) tone.

Key Words: resistance arteries • myogenic tone • Notch receptors • flow-mediated dilation • local blood flow regulation

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