Abstract
Angiogenesis plays a critical role in the progression and vulnerability of atherosclerotic plaques; however, the orchestration of angiogenesis in atherosclerotic plaque formation remains unclear. The results of microarray analysis, real-time PCR and immunohistochemical analyses showed that Hairy/enhancer of split homologue-1 (Hes-1) expression was significantly decreased, while that of osteopontin (OPN) was increased, in atherosclerotic plaques. Meanwhile, immunofluorescence results demonstrated that both Hes-1 and OPN were expressed in endothelial cells (ECs) of neovessels in atherosclerotic plaques. The results of an in vitro study showed that Hes-1 was downregulated, while OPN was upregulated, in a time- and dose-dependent manner in human umbilical vein endothelial cells (HUVECs) by VEGF treatment. In addition, Hes-1 knockdown was found to have transcriptional promotion effect on OPN expression in HUVECs and enhance OPN-induced angiogenesis in response to VEGF. On the contrary, Hes-1 overexpression inhibited OPN expression in HUVECs and reduced angiogenesis in vitro and in vivo. The results of this study suggest that decreased Hes-1 expression in atherosclerotic plaques exaggerate VEGF-induced angiogenesis by upregulating OPN. Therefore, restoring Hes-1 expression and inhibiting OPN expression may be a promising strategy to prevent vulnerable plaque formation in patients with atherosclerosis.
Highlights
Renal artery atherosclerosis V demonstrated that Hes-1 expression is regulated in confluent endothelial cells (ECs) by the JNK signaling pathway, which induces EC growth arrest
Vascular endothelial growth factor (VEGF) produced by inflammatory cells and/or ECs has been implicated in the initiation of intraplaque angiogenesis and promotion of plaque formation, which eventually results in intraplaque hemorrhage[16]
The results revealed that Hes-1 was decreased by 20.68-fold (p < 0.005) in atherosclerotic plaques
Summary
Down-regulation of Hes-1 in human atherosclerotic plaques. Hes-1 plays an important role in angiogenesis[8]. The results of real-time PCR analysis showed that Hes-1 mRNA levels were significantly lower in atherosclerotic plaques than in normal arterial intima tissues (Fig. 1A). The promoting effects of VEGF on OPN expression were gradually enhanced in a time-dependent manner, with the greatest effect observed at 24 h after VEGF treatment (Fig. 3B) These results indicated that the OPN upregulation observed in atherosclerotic plaques was probably regulated by VEGF. After VEGF treatment, the elevation in OPN protein levels by VEGF was markedly compensated by Hes-1 overexpression These data demonstrated that Hes-1 was a transcriptional mediator of VEGF-regulated OPN expression and that VEGF upregulated OPN partially through the downregulation of Hes[1], indicating that decreased Hes-1 expression contributed to the increase in OPN expression in VEGF-treated HUVECs and likely in atherosclerotic plaques. These data revealed Hes-1 as a negative regulator of VEGF-induced angiogenesis through regulating OPN
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
