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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:488.)
© 2006 American Heart Association, Inc.

Vascular Biology

Thromboxane A2/Prostaglandin H2 Receptor Activation Mediates Angiotensin II–Induced Postischemic Neovascularization

Frédéric Michel; Jean-Sébastien Silvestre; Ludovic Waeckel; Stefano Corda; Tony Verbeuren; Jean Paul Vilaine; Michel Clergue; Micheline Duriez; Bernard I. Levy

From the Cardiovascular Research Center INSERM U689 Lariboisière (F.M., J.-S.S., L.W., M.C., M.D., B.I.L.), Université Paris, Paris, France; and the Institut de Recherches Servier (S.C., T.V., J.P.V.), Suresnes, France.

Correspondance to Bernard Levy or Jean-Sebastien Silvestre, U689-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail levy{at}larib.inserm.fr or Jean-Sebastien.Silvestre@larib.inserm.fr

Objective— We analyzed the involvement of thromboxane (TX) A₂/prostaglandin (PG) H₂ (TP) receptor in ischemia-induced neovascularization in mice.

Methods and Results— Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days. Hindlimb ischemia raised plasma level of TXB_2, the stable metabolite of TXA₂, by 4.7-fold. This increase was blocked by aspirin treatment whereas S18886 (5 or 10 mg/kg per day) had no effect. However, neither S 18886 nor aspirin affected postischemic neovascularization. We next assessed the putative involvement of TXA₂ signaling in angiotensin II (Ang II) proangiogenic pathway. Ang II (0.3 mg/kg per day) enhanced TXB₂ plasma levels by 2.6-fold over that of control (P<0.01). Ang II-induced TXB₂ upregulation was reduced by cotreatment with Ang II type I receptor antagonist (candesartan, 20 mg/kg per day). Angiographic score, capillary number, and foot perfusion were improved by 1.7-, 1.7-, and 1.4-fold, respectively, in Ang II-treated mice compared with controls (P<0.05). Ang II proangiogenic effect was associated with a 1.6-fold increase in VEGF-A protein content (P<0.05) and a 1.4-fold increase in the number of Mac-3–positive cells (ie, macrophages) in ischemic areas (P<0.05). Interestingly, treatments with TP receptor antagonists or aspirin hampered the proangiogenic effects of Ang II.

Conclusion— Endogenous activation of TXA₂ receptor by eicosanoids did not modulate spontaneous neovascularization in the setting of ischemia. Conversely, TXA₂ signaling is involved in Ang II-induced AT1-dependent vessel growth.

Endogenous activation of TXA₂ receptor by eicosanoids did not modulate spontaneous neovascularization in the setting of ischemia. In contrast, treatments with TP receptor antagonists or aspirin hampered the proangiogenic effect of Ang II and fully abrogated the Ang II-induced increase in VEGF-A protein content and the number of Mac-3–positive cells.

Key Words: angiogenesis • angiotensin II • ischemia • thromboxane A₂