Up-regulation of FGFBP1 signaling contributes to miR-146a-induced angiogenesis in human umbilical vein endothelial cells

Abstract

Recent microRNA expression profiling studies have documented an up-regulation of miR-146a in several angiogenesis models. However, the underlying molecular mechanism of miR-146a in the angiogenic activity of endothelial cells has not been clearly elucidated. The present study was aimed to evaluate whether miR-146a promotes angiogenesis in HUVECs by increasing FGFBP1 expression via directly targeting CREB3L1. miR-146a was over expressed in HUVECs via lentiviral-miR-146a. Expression profiling analysis found miR-146a over expression resulted in up-regulation of angiogenesis and cytokine activity associated genes including FGF2. Further a combination of bioinformatics and experimental analyses demonstrated the CREB3L1 as a bona fide functional target of miR-146a during angiogenesis. Moreover, CREB3L1 inhibited luciferase expression from FGFBP1 promoter containing only CRE elements. Furthermore, CREB3L1 inhibited FGFBP1 expression by binding to two CRE-like sites located at approximately −1780–1777 and −868–865 bp relative to the FGFBP1 transcription start site. Additionally, ectopic expression of CREB3L1 decreased miR-146a-induced FGF2 secretion. These findings indicate that the miR-146a-CREB3L1-FGFBP1 signaling axis plays an important role in the regulation of angiogenesis in HUVECs and provides a potential therapeutic target for anti-angiogenic therapeutics.

MicroRNA-146a Regulates Perfusion Recovery in Response to Arterial Occlusion via Arteriogenesis

“…One previous report found that inhibition of miR-146a led to increased capillary sprouting in both aortic ring and laser-induced choroidal neovascularization assays (Halkein et al, 2013 ). In contrast, several previous studies have found that loss of miR-146a impairs angiogenesis in vitro (Zhu et al, 2013 , 2016 ; Rau et al, 2014 ; Li et al, 2017 ), which would suggest miR-146a inhibition should impair perfusion recovery. In our hands, in vitro miR-146a inhibition attenuated both network-like formation and EC migration while there was no effect on EC survival or permeability.…”

“…To this end, inhibition of miR-100 has been shown previously to enhance perfusion recovery following FAL (Grundmann et al, 2011 ), and we have recently determined that miR-199a inhibition is a potent enhancer of perfusion recovery and arteriogenesis following FAL in Balb/c mice (Heuslein and Price, 2017 ). Though miR-146a has been shown to be enriched in ECs in vivo (Cheng et al, 2013 ) and to regulate both endothelial activation (Cheng et al, 2013 ) and in vitro angiogenesis (Zhu et al, 2013 , 2016 ; Rau et al, 2014 ), the role of miR-146a following FAL is unknown. Here, we tested the hypothesis that miR-146a regulates angiogenesis, arteriogenesis, and perfusion recovery after FAL.…”

MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice

“…Thus, our data suggest that miR-146 mimics suppress NF-κB signaling-activated inflammation via its target genes, IRAK and TRAF6, and consequently reduce thrombosis, leading to improved peripheral tissue perfusion. Others have shown that miR-146a increases angiogenesis in human umbilical vein endothelial cells ( 44 ). Thus, the effects of miR-146a on vascularization in sciatic nerves of diabetic mice warrant further study.…”

Reduced Plasma miR-146a Is a Predictor of Poor Coronary Collateral Circulation in Patients with Coronary Artery Disease

“…Other reports have demonstrated that miR-146a enhances the angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting the expression of platelet-derived growth factor receptor α [12]. In addition, miR-146a induces angiogenesis in human umbilical vein endothelial cells via upregulation of FGFBP1 signaling [13]. …”