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(Circulation Research. 2002;90:820.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Smooth Muscle Dysfunction in Resistance Arteries of the Staggerer Mouse, a Mutant of the Nuclear Receptor ROR

Sandrine Besnard, Joëlle Bakouche, Yolande Lemaigre-Dubreuil, Jean Mariani, Alain Tedgui, Daniel Henrion

From INSERM U541, IFR Circulation-Paris 7, Université Paris 7, Paris, France; and CNRS UMR7102 and Université Paris 6 (J.B., Y.L.-D., J.M.), Neurobiologie des Processus Adaptatifs, Paris, France.

Correspondence to Alain Tedgui, INSERM U541, Hopital Lariboisiere, 41 Bd de la Chapelle, 75475 Paris, cedex 10, France. E-mail alain.tedgui{at}inserm.lrb.ap-hop-paris.fr

Retinoic acid receptor–related orphan receptor (ROR) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the ROR gene. ROR plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1±1.2 and 87.0±0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional ROR is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that ROR might be involved in the differentiation of SMCs in mesenteric arteries.

Key Words: ROR&agr • nuclear receptors • vascular reactivity • resistance arteries • differentiation markers

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