Objective-We analyzed the involvement of thromboxane (TX) A 2 /prostaglandin (PG) H 2 (TP) receptor in ischemiainduced neovascularization in mice. Methods and Results-Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (nϭ7 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 TXA 2 , 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 TXA 2 signaling in angiotensin II (Ang II) proangiogenic pathway. Ang II (0.3 mg/kg per day) enhanced TXB 2 plasma levels by 2.6-fold over that of control (PϽ0.01). Ang II-induced TXB 2 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 (PϽ0.05). Ang II proangiogenic effect was associated with a 1.6-fold increase in VEGF-A protein content (PϽ0.05) and a 1. Key Words: angiogenesis Ⅲ angiotensin II Ⅲ ischemia Ⅲ thromboxane A 2 N eovascularization occurs in response to local tissue ischemia mainly through inflammation and hypoxia signaling. One mechanism by which hypoxia activates blood vessel growth is the increase in hypoxia-inducible factor (HIF-1␣) leading to the expression of key growth factors, including vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF). 1 Macrophages and T lymphocytes also promote neovascularization in ischemic areas through the release of proinflammatory cytokines, production of matrix metalloproteinases, and expression of angiogenic factors. [2][3][4] Neovascularization takes place in the context of cross-talk involving numerous factors. Among them, hormones such as angiotensin II (Ang II) have been shown to modulate postischemic neovascularization by activation of Ang II type I receptor (AT1) and upregulation of VEGF-A signaling. 5,6 Ang II also enhances macrophage infiltration and subsequently inflammation-dependent vessel growth. 6 -8 Thromboxane A 2 (TXA 2 ) is an unstable metabolite of arachidonic acid formed through the cyclooxygenase pathway. TXA 2 is released from activated platelets, monocytes, and damaged vessel wall, and causes platelet aggregation, vasoconstriction, and hypertrophy of vascular smooth muscle. 9 Action of TXA 2 is mediated by thromboxane A 2 /PG H 2 receptor (TP receptor), which are also able to bind other endogenous ligands such as endoperoxides and isoprostanes. TP receptors are widely expressed in the vasculature and exist as 2 isoforms TP␣ and TP in humans, whereas only TP␣ is present in rodents. 10 As in many vasoconstrictive substances,...