Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis

Abstract

6 Besides the VEGF pathway, the superfamily of fibroblast growth factors (FGFs) is wellknown as potent inducer of neovascularization. In humans and mice, 22 FGF ligands and 4 tyrosine kinase highaffinity FGF receptors (FGFR1-4) have been identified; however, in endothelial cells, FGFR1 is the predominantly expressed FGFR. 7,8 Regarding the cardiovascular system, © 2014 American Heart Association, Inc. Objective-Previously, we have identified bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation. Approach and Results-To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper +/− mice. Aortic ring assays of C57BL/6_Bmper +/− mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. Conclusions-Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis. 7,10,11 In addition to the FGF and VEGF growth factors, other growth factor families, such as the transforming growth factor-β (TGF-β) superfamily comprising the bone morphogenetic proteins (BMPs), contribute to the proper orchestration of blood vessel formation. 12,13 BMPs are extracellular proteins that signal through cell surface complexes of heterodimeric transmembrane serine/ threonine kinase receptors. On activation of the receptor, Smad 1/5 transcription factors become phosphorylated and translocate to the nucleus where they modulate gene expression.14 Besides this Smad-dependent pathway, BMPs also phosphorylate other Smad-independent signaling cascades, such as MAP kinases/Erk and phosphoinositide 3-ki...

Mimicking the Bioactivity of Fibroblast Growth Factor-2 Using Supramolecular Nanoribbons

“…This type of nuclear localization of p-FGFR1 has been observed before when the receptor is activated. 63 These images further confirm the effective activation of FGFR1 by FGF2-PA nanoribbons with complementary SEM images suggesting interactions between the FGF2-PA nanoribbons and cell surfaces (Figure S13). …”

Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial‐venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells

“…During the last few years, BMPER has emerged to be in the focus of interest in vascular biology [20][21][22][23][24][25][26]. Regarding angiogenesis, we and others have previously shown that BMPER may enhance BMP signaling and the angiogenic response of endothelial cells in a concentration-dependent manner [23,26,27]. Along the same line, BMPER was recently shown to be indispensable for normal coronary artery plexus formation during mouse embryonic development [25].…”

“…BMPER, the vertebrate homolog of Drosophila crossveinless 2, is a secreted glycoprotein that contains five cysteine-rich domains followed by a von Willebrand D domain and a trypsin inhibitor domain and was originally identified in a screen for differentially expressed proteins in embryonic endothelial precursor cells [17]. During the last few years, BMPER has emerged to be in the focus of interest in vascular biology [20][21][22][23][24][25][26]. Regarding angiogenesis, we and others have previously shown that BMPER may enhance BMP signaling and the angiogenic response of endothelial cells in a concentration-dependent manner [23,26,27].…”

Gambogic acid impairs tumor angiogenesis by targeting YAP/STAT3 signaling axis

“…It has been well documented that tumor angiogenesis relies on angiogenic molecules and the transduction of their signals in ECs (Welti, Loges, Dimmeler, & Carmeliet, ). A growing body of evidence has indicated that pivotal ligands/receptors, including vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), fibroblast growth factor (FGF)/FGF receptor (FGFR), platelet‐derived growth factor (PDGF)/PDGF receptor (PDGFR), angiopoietin/TIE2, and delta‐like 4 (DLL4)/Notch, are effectively and coordinately involved to modulate such complicated angiogenic process (Esser et al, ; Felcht et al, ; Li et al, ; Shibuya, ; Wang et al, ). Among all these known angiogenic factors, VEGF and its receptors (VEGFR) are recognized as fundamental stimuli of tumor angiogenesis (Shibuya, ).…”