Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR 72205, USA.
J Cardiovasc Pharmacol Ther. 2011 Mar;16(1):105-10. doi: 10.1177/1074248410378505. Epub 2010 Oct 12.
Hypoxia-reoxygenation (HR) is a major driver for angiogenesis in atherosclerotic plaques and tumors. Angiogenesis is a multistep process requiring stimulation of proliferation and migration of endothelial cells in response to a number of growth factors, including transforming growth factor (TGFβ1). Aspirin (acetylsalicylic acid) has been shown to reduce atherosclerosis-related events as well as development of certain tumors. We examined the role of aspirin in HR-mediated angiogenesis from human umbilical vein endothelial cells (HUVECs). We found that aspirin (0.5 and 1 mmol/L) markedly (by about 30%, P < .01) reduced HR-mediated tube formation. Next, we studied changes in TGFβ1 and its type 1 receptor (TGFβ-R1) as well as in the transcription of p53 and p21 during HR-mediated angiogenesis. Hypoxia-reoxygenation modestly increased TGFβ1 and decreased its type 1 receptor (TGFβ-R1) transcription (both P-NS) and reduced the transcription of p53 and p21 (P < .05). Treatment of HUVECs with aspirin suppressed TGFβ1 and enhanced TGFβ-R1 mRNA expression during HR (both P < .05 vs HR alone) without a change in p53 and p21 (P-NS). In other experiments, treatment of cells with TGFβ1 antibody modestly decreased HR-mediated angiogenesis; however, TGFβ1 antibody treatment significantly enhanced the inhibitory effect of aspirin on tube formation. Based on these data, we suggest that the inhibitory effect of aspirin on HR-mediated angiogenesis involves TGFβ1-TGFβ-R1 pathway.
缺氧复氧（HR）是动脉粥样硬化斑块和肿瘤血管生成的主要驱动因素。血管生成是一个多步骤的过程，需要刺激内皮细胞的增殖和迁移，以响应多种生长因子，包括转化生长因子（TGFβ1）。阿司匹林（乙酰水杨酸）已被证明可减少与动脉粥样硬化相关的事件以及某些肿瘤的发展。我们研究了阿司匹林在人脐静脉内皮细胞（HUVEC）中 HR 介导的血管生成中的作用。我们发现阿司匹林（0.5 和 1 mmol/L）显著（约 30%，P <.01）降低了 HR 介导的管形成。接下来，我们研究了 HR 介导的血管生成过程中 TGFβ1 及其 1 型受体（TGFβ-R1）以及 p53 和 p21 的转录变化。缺氧复氧适度增加了 TGFβ1 并降低了其 1 型受体（TGFβ-R1）转录（均 P-NS），并降低了 p53 和 p21 的转录（P <.05）。用阿司匹林处理 HUVEC 可在 HR 期间抑制 TGFβ1 并增强 TGFβ-R1 mRNA 表达（均 P <.05 与 HR 单独相比），而 p53 和 p21 无变化（P-NS）。在其他实验中，用 TGFβ1 抗体处理细胞可适度降低 HR 介导的血管生成；然而，TGFβ1 抗体处理显著增强了阿司匹林对管形成的抑制作用。基于这些数据，我们认为阿司匹林对 HR 介导的血管生成的抑制作用涉及 TGFβ1-TGFβ-R1 途径。
