Tumor angiogenesis plays a vital role in carcinogenesis, cancer progression, and metastasis. Lipoxin A₄ (LXA₄) is an endogenously-produced family of effective anti-inflammatory with a potent inhibitory effect on angiogenesis. However, BML-111, a LXA₄ agonist, its governing tumor-derived endothelial cells (Td-EC) mechanisms remain unknown. In the present study, we utilized VEGF or CoCl₂ to mimic tumor microenvironment in vitro to study the effect of BML-111 on angiogenesis and permeability of Td-EC, and preliminarily explore its specific mechanism. Data suggested that BML-111 inhibited viability, migration and angiogenesis in VEGF or CoCl₂-treated Td-EC by modulating MMP2/9-TIMP1, and decreasing the production of HIF-1α and COX-2 level. In addition, we observed that BML-111 inhibited Td-EC permeability induced by VEGF or CoCl₂, through the stabilization of VE-cadherin/β-catenin-dependent adherens junctions and TRPC1 pathway. Nevertheless, these effects could be blocked by BOC-2 which was the specific inhibitor of FPR2/ALX (the receptor of LXA₄).These results suggest that BML-111 may have inhibitory effects on VEGF or CoCl₂-induced migration, angiogenesis and permeability in tumor-derived endothelial cells.

肿瘤血管生成在癌发生、癌症进展和转移中起着至关重要的作用。脂氧素 A ₄ (LXA ₄ ) 是一种内源性产生的有效抗炎剂家族，对血管生成具有强效抑制作用。然而，BML-111，一种 LXA ₄激动剂，其调控肿瘤衍生内皮细胞 (Td-EC) 的机制仍然未知。本研究利用VEGF或CoCl ₂体外模拟肿瘤微环境，研究BML-111对Td-EC血管生成和通透性的影响，初步探索其具体机制。数据表明 BML-111 抑制 VEGF 或 CoCl _{2中的活力、迁移和血管生成}-通过调节 MMP2/9-TIMP1 并降低 HIF-1α 和 COX-2 水平的产生来处理 Td-EC。此外，我们观察到 BML-111通过稳定 VE-钙粘蛋白/β-连环蛋白依赖性粘附连接和 TRPC1 通路，抑制由 VEGF 或 CoCl _{2诱导的 Td-EC 通透性。}然而，这些作用可以被 BOC-2 阻断，BOC-2 是 FPR2/ALX（LXA ₄的受体）的特异性抑制剂。这些结果表明 BML-111 可能对 VEGF 或 CoCl ₂诱导的迁移、血管生成和肿瘤衍生内皮细胞的通透性。