Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.

Abstract

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 TXB2, 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.

CONCLUSIONS:

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.

• Authors: Frédéric Michel, Jean-Sébastien Silvestre, Ludovic Waeckel, Stefano Corda, Tony Verbeuren, Jean Paul Vilaine, Michel Clergue, Micheline Duriez, Bernard I Levy
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 3 Pg. 488-93 (Mar 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16385086 (Publication Type: Journal Article)

Chemical References

• Naphthalenes
• Propionates
• Receptors, Thromboxane A2, Prostaglandin H2
• Vasoconstrictor Agents
• Angiotensin II
• Thromboxane B2
• Thromboxane A2
• terutroban

Topics

• Angiotensin II (blood, pharmacology)
• Animals
• Capillaries (physiology)
• Hindlimb (blood supply)
• Ischemia (metabolism, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Naphthalenes (pharmacology)
• Neovascularization, Physiologic (drug effects, physiology)
• Propionates (pharmacology)
• Receptors, Thromboxane A2, Prostaglandin H2 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects, physiology)
• Thromboxane A2 (blood)
• Thromboxane B2 (blood)
• Vasculitis (metabolism, physiopathology)
• Vasoconstrictor Agents (blood, pharmacology)