Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.
OBJECTIVE
We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice.


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.
Michel
Frédéric
F
Cardiovascular Research Center INSERM U689 Lariboisière, Université Paris, Paris, France.
Silvestre
Jean-Sébastien
JS
Waeckel
Ludovic
L
Corda
Stefano
S
Verbeuren
Tony
T
Vilaine
Jean Paul
JP
Clergue
Michel
M
Duriez
Micheline
M
Levy
Bernard I
BI
D000804:Angiotensin II / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013928:Thromboxane A2 / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D014657:Vasculitis / Q000378:metabolism / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000097:blood* / Q000494:pharmacology
D009281:Naphthalenes; D011422:Propionates; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013929:Thromboxane B2; D013928:Thromboxane A2; C501362:terutroban