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(Circulation Research. 2001;89:1209.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Increased Ischemia-Induced Angiogenesis in the Staggerer Mouse, a Mutant of the Nuclear Receptor Ror

Sandrine Besnard, Jean-Sébastien Silvestre, Micheline Duriez, Joëlle Bakouche, Yolande Lemaigre-Dubreuil, Jean Mariani, Bernard I. Levy, Alain Tedgui

From INSERM U541, Hôpital Lariboisière, and IFR Circulation-Paris 7, Université Paris 7-Denis Diderot (S.B., J.-S.S., M.D., B.I.L., A.T.), France; and CNRS et Université Pierre et Marie Curie (J.B., Y.L.-D., J.M.), FRE 2371 Neurobiologie des Processus Adaptatifs, Laboratoire DVSN, Paris, France.

Correspondance to Alain Tedgui, U541-INSERM, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail tedgui{at}infobiogen.fr

Ror is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rora^sg/sg), a deletion within the Rora gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Rora^+/+ and Rora^sg/sg mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Rora^sg/sg mice and in Rora^+/+ littermates. Conversely, at day 28, Rora^sg/sg mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Rora^sg/sg mice (0.83±0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror^+/+ mice (0.66±0.04, P<0.05). In addition, more extensive angiogenesis in Rora^sg/sg mice correlated with an increased expression of eNOS protein by 83±12% and 71±24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38±10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror as a potent negative regulator of ischemia-induced angiogenesis.

Key Words: Ror • nuclear receptors • angiogenesis • ischemia • inflammation

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