Bone Morphogenetic Protein Endothelial Cell Precursor–Derived Regulator Regulates Retinal Angiogenesis In Vivo in a Mouse Model of Oxygen-Induced Retinopathy

Moreno–Miralles, Isabel; Ren, Rongqin; Moser, Martin; Hartnett, M. Elizabeth; Patterson, W. Cam

doi:10.1161/atvbaha.111.230235

Cited by 36 publications

(45 citation statements)

References 37 publications

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“…This hypothesis is strengthened by the recent observation that this gene, mainly devoted to osteogenic differentiation, could be potentially proangiogenic being involved in the regulation of vessel development. 48 In the present study we also examined how IGF1 or IG-F1/VEGF could affect MAPK and PI3K/AKT pathways, which are both critical for appropriate cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Role of IGF1 and IGF1/VEGF on Human Mesenchymal Stromal Cells in Bone Healing: Two Sources and Two Fates

FerrettiConcetta

Vozzi

FalconiMirella

et al. 2014

Tissue Engineering Part A

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In the repair of skeletal defects one of the major obstacles still remains an efficient vascularization of engineered scaffolds. We have examined the ability of insulin growth factor-1, alone or in association with vascular endothelial growth factor, to modulate the osteoblastic or endothelial commitment of periosteum-derived progenitor cells (PDPCs) and skin-derived multipotent stromal cells (S-MSCs). A selected gene panel for endothelial and osteoblastic differentiation as well as genes that can affect MAPK and PI3K/AKT signaling pathways were investigated. Moreover, gene expression profile of Sox2, Oct4, and Nanog transcription factors was assessed. Our results showed that under growth factor stimulation PDPCs are induced toward an osteoblastic differentiation, while S-MSCs seem to move along an endothelial phenotype. This different commitment seems to be linked to a diverse MAPK or PI3K/AKT signaling pathway activation. The analysis of genes for stemness evidenced that at least in PDPCs multipotency and differentiation could coexist. These results open interesting perspective for the development of innovative bone tissue engineering approaches based on a good network of angiogenesis and osteogenesis processes.

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Section: Discussionmentioning

confidence: 99%

Role of IGF1 and IGF1/VEGF on Human Mesenchymal Stromal Cells in Bone Healing: Two Sources and Two Fates

FerrettiConcetta

Vozzi

FalconiMirella

et al. 2014

Tissue Engineering Part A

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“…Generally, ERK1,2 signaling is considered to induce cell proliferation, and its signaling pathway is activated by various growth factors and cytokines, 24 including BMP4. 47,48 Recently, Chiu et al 6 revealed that when BMP4 activated ERK1,2 signaling via BMP receptor II (Smad-independent pathway), human hepatocarcinoma cells were stimulated to proliferate and migrate. On the other hand, when BMP4 phosphorylated Smad1,5 through the BMP receptor IA (Smad-dependent pathway), the proliferation of these cells was inhibited.…”

Section: Discussionmentioning

confidence: 99%

BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors

et al. 2013

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Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy.

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“…18,[23][24][25] 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.…”

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confidence: 94%

“…17 During the last few years, BMPER has emerged to be in the focus of interest in vascular biology, including endothelial cell inflammation, 21 atherosclerosis, 22 and angiogenesis. 18,[23][24][25] 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. 19,23 Along the same line, BMPER was recently shown to be indispensable for normal coronary artery plexus formation during mouse embryonic development.…”

mentioning

confidence: 94%

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

Esser

Rahner

Deckler

et al. 2015

ATVB

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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...

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Bone Morphogenetic Protein Endothelial Cell Precursor–Derived Regulator Regulates Retinal Angiogenesis In Vivo in a Mouse Model of Oxygen-Induced Retinopathy

Cited by 36 publications

References 37 publications

Role of IGF1 and IGF1/VEGF on Human Mesenchymal Stromal Cells in Bone Healing: Two Sources and Two Fates

Role of IGF1 and IGF1/VEGF on Human Mesenchymal Stromal Cells in Bone Healing: Two Sources and Two Fates

BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors

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

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