Increased Ischemia-Induced Angiogenesis in the Staggerer Mouse, a Mutant of the Nuclear Receptor Rorα (original) (raw)

2001, Circulation Research

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 ϩ/ϩ 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 ϩ/ϩ 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 (0.83Ϯ0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror ϩ/ϩ mice (0.66Ϯ0.04, PϽ0.05). In addition, more extensive angiogenesis in Rora sg/sg mice correlated with an increased expression of eNOS protein by 83Ϯ12% and 71Ϯ24% at 3 and 28 days, respectively (PϽ0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38Ϯ10% at day 28 (PϽ0.05). 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.