Angiostatic Effects of Aspirin in Hypoxia-Reoxygenation Are Linked to Modulation of TGFβ1 Signaling

Abstract

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.

Keywords

aspirin angiogenesis endothelial cells transforming growth factor

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