| First Author | Besnard S | Year | 2001 |
| Journal | Circ Res | Volume | 89 |
| Issue | 12 | Pages | 1209-15 |
| PubMed ID | 11739287 | Mgi Jnum | J:115425 |
| Mgi Id | MGI:3691562 | Doi | 10.1161/hh2401.101755 |
| Citation | Besnard S, et al. (2001) Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha. Circ Res 89(12):1209-15 |
| abstractText | Ror alpha is an orphan nuclear receptor. In homozygous staggerer mutant mice (Ror alpha(sg/sg)), a deletion within the Ror alpha 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 alpha in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Ror alpha(+/+) and Ror alpha(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 Ror alpha(sg/sg) mice and in Ror alpha(+/+) littermates. Conversely, at day 28, Ror alpha(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 Ror alpha(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 Ror alpha(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 alpha as a potent negative regulator of ischemia-induced angiogenesis. |
