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

Abstract

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,...

Rationale and Design of a Randomized, Double-Blind, Parallel-Group Study of Terutroban 30 mg/day versus Aspirin 100 mg/day in Stroke Patients: The Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) Study

“…Animal studies have shown that terutroban has beneficial effects on platelet aggregation, thrombus formation, vascular reactivity, and vessel wall proliferation [21,22,23]. In rabbits, it reduces the size of atherosclerotic plaque, intima-media thickness, intracellular adhesion molecule expression in endothelial cells, and monocyte/macrophage infiltration in the vessel walls [24].…”

Involvement of COX2–thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish

“…Otherwise, low concentrations of TP agonists induce the angiogenesis in vitro , while high doses of TP agonists produce a biphasic response (Nie et al, 2000; Benndorf et al, 2008). There also is evidence suggesting that TBXA2 has opposite effects on angiogenesis depending upon the thromboxane receptor isoforms, a and b, in human endothelial cells (Ashton and Ware, 2004; Michel et al, 2006). At present, properties of zebrafish TP receptor are unknown.…”

Activation of Thromboxane Receptor Mediates Interleukin-8 Expression in Endothelial Cells

“…2(b)). 혈관내피세포막에 존재하는 TXA 2 수용체의 isoform의 종류는 α isoform과 β isoform이 존재한다고 알려져 있다 [15,16]. 트롬복산 수용체 작용제가 혈관내피세포를 자극하여 IL-8 발현 및 ERK1/2와 p38 신호전달 경로를 활성화 시킬 때 어떠한 종류의 막 수용 체의 isoform이 작용하는 지에 대한 연구는 추가적인 실험을 통해 규명해 낼 필요가 있을 것으로 생각된다.…”

“…이러한 혈관 내피세포에서의 TXA 2 의 기능은 혈관내피세포막에 존재하 는 트롬복산 수용체 (thromboxane receptor, TP)를 통해 작용 한다. 트롬복산 수용체는 인간에서는 TPα과 TPβ, 두 가지 isoform을 가지고 있으며 이들의 활성이 죽상동맥경화증과 같은 혈관성 염증질환에 관여한다 [15,16]. 그리고 트롬복산 수용체의 발현 및 트롬복산 수용체의 리간드의 혈장 농도가 여러 가지 심혈관계 질환에서 증가되어 있다고 보고되고 있 다 [17,18].…”