The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform
Martin Moser - One of the best experts on this subject based on the ideXlab platform.
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Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Jennifer S. Esser, Christoph Bode, Cam Patterson, S. Rahner, Meike Deckler, Martin MoserAbstract: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-...
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Abstract 555: Bone Morphogenetic Protein Modulator BMPER Induces Angiogenesis via Inhibition of Thrombospondin-1 and Activation of the Fibroblast Growth Factor Signaling Pathway
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Jennifer S. Esser, Christoph Bode, S. Rahner, Meike Deckler, Martin MoserAbstract:Introduction: Bone morphogenetic proteins (BMP) play a key role in vascular development. Previously, we have identified BMP Endothelial Cell Precursor-derived regulator (BMPER), an extraCellular BMP modulator, to increase the angiogenic activity of Endothelial Cells in a concentration-dependent manner. In this project we now investigate how the BMPER effect is mediated by key molecules of angiogenesis. Methods and Results: To assess the effect of BMPER on angiogenesis-related molecules we performed an angiogenesis antibody array with BMPER-stimulated human umbilical venous Endothelial Cells (HUVECs) and vice versa with BMPER-silenced HUVECs compared to control conditions, respectively. We detected increased protein expression of the anti-angiogenic thrombospondin-1 (TSP-1) 48 hours after siBMPER transfection and, consistently, decreased TSP-1 expression after stimulation with BMPER (60 ng/ml; 39% ± 7.3 N=4). Furthermore, the pro-angiogenic protein bFGF was increased after BMPER stimulation, which was conf...
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BMPER-induced BMP signaling promotes coronary artery remodeling.
Developmental biology, 2013Co-Authors: Laura A. Dyer, Martin Moser, Cam PattersonAbstract:The connection of the coronary vasculature to the aorta is one of the last essential steps of cardiac development. However, little is known about the signaling events that promote normal coronary artery formation. The bone morphogenetic protein (BMP) signaling pathway regulates multiple aspects of Endothelial Cell biology but has not been specifically implicated in coronary vascular development. BMP signaling is tightly regulated by numerous factors, including BMP-binding Endothelial Cell Precursor-derived regulator (BMPER), which can both promote and repress BMP signaling activity. In the embryonic heart, BMPER expression is limited to the Endothelial Cells and the Endothelial-derived cushions, suggesting that BMPER may play a role in coronary vascular development. Histological analysis of BMPER(-/-) embryos at early embryonic stages demonstrates that commencement of coronary plexus differentiation is normal and that Endothelial apoptosis and Cell proliferation are unaffected in BMPER(-/-) embryos compared with wild-type embryos. However, analysis between embryonic days 15.5-17.5 reveals that, in BMPER(-/-) embryos, coronary arteries are either atretic or connected distal to the semilunar valves. In vitro tubulogenesis assays indicate that isolated BMPER(-/-) Endothelial Cells have impaired tube formation and migratory ability compared with wild-type Endothelial Cells, suggesting that these defects may lead to the observed coronary artery anomalies seen in BMPER(-/-) embryos. Additionally, recombinant BMPER promotes wild-type ventricular Endothelial migration in a dose-dependent manner, with a low concentration promoting and high concentrations inhibiting migration. Together, these results indicate that BMPER-regulated BMP signaling is critical for coronary plexus remodeling and normal coronary artery development.
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Antagonism and synergy between extraCellular BMP modulators Tsg and BMPER balance blood vessel formation
Journal of Cell Science, 2013Co-Authors: Jennifer Heinke, Thomas Helbing, Christoph Bode, Cam Patterson, Maria Juschkat, Anne Charlet, Leonie Mnich, Martin MoserAbstract:Summary Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extraCellular BMP modulators such as BMP Endothelial Cell Precursor derived regulator (BMPER), which we reported previously acts proangiogenically on Endothelial Cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on Endothelial Cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein Endothelial Cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on Endothelial Cells. Tsg enhanced Endothelial Cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro , dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular Cell homeostasis.
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LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the Bmp System in Endothelial Cells and in Angiogenesis
Circulation research, 2012Co-Authors: Christopher E. Schmitt, Martin Moser, Pamela Lockyer, Liang Xie, Andrea L. Portbury, Laura A. Dyer, Edward J. FlynnAbstract:Rationale: Among the extraCellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp Endothelial Cell Precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and–sink mechanism. Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper9s differential effects on Bmp4 signaling. Methods and Results: Using an array of biochemical and Cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper9s ability to fine-tune Bmp4 signaling at the single-Cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.
Christoph Bode - One of the best experts on this subject based on the ideXlab platform.
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Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Jennifer S. Esser, Christoph Bode, Cam Patterson, S. Rahner, Meike Deckler, Martin MoserAbstract: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-...
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Abstract 555: Bone Morphogenetic Protein Modulator BMPER Induces Angiogenesis via Inhibition of Thrombospondin-1 and Activation of the Fibroblast Growth Factor Signaling Pathway
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Jennifer S. Esser, Christoph Bode, S. Rahner, Meike Deckler, Martin MoserAbstract:Introduction: Bone morphogenetic proteins (BMP) play a key role in vascular development. Previously, we have identified BMP Endothelial Cell Precursor-derived regulator (BMPER), an extraCellular BMP modulator, to increase the angiogenic activity of Endothelial Cells in a concentration-dependent manner. In this project we now investigate how the BMPER effect is mediated by key molecules of angiogenesis. Methods and Results: To assess the effect of BMPER on angiogenesis-related molecules we performed an angiogenesis antibody array with BMPER-stimulated human umbilical venous Endothelial Cells (HUVECs) and vice versa with BMPER-silenced HUVECs compared to control conditions, respectively. We detected increased protein expression of the anti-angiogenic thrombospondin-1 (TSP-1) 48 hours after siBMPER transfection and, consistently, decreased TSP-1 expression after stimulation with BMPER (60 ng/ml; 39% ± 7.3 N=4). Furthermore, the pro-angiogenic protein bFGF was increased after BMPER stimulation, which was conf...
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Antagonism and synergy between extraCellular BMP modulators Tsg and BMPER balance blood vessel formation
Journal of Cell Science, 2013Co-Authors: Jennifer Heinke, Thomas Helbing, Christoph Bode, Cam Patterson, Maria Juschkat, Anne Charlet, Leonie Mnich, Martin MoserAbstract:Summary Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extraCellular BMP modulators such as BMP Endothelial Cell Precursor derived regulator (BMPER), which we reported previously acts proangiogenically on Endothelial Cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on Endothelial Cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein Endothelial Cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on Endothelial Cells. Tsg enhanced Endothelial Cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro , dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular Cell homeostasis.
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BMPER Is Upregulated by Statins and Modulates Endothelial Inflammation by InterCellular Adhesion Molecule–1
Arteriosclerosis thrombosis and vascular biology, 2009Co-Authors: Thomas Helbing, Jennifer Heinke, Christoph Bode, Cam Patterson, Rene Rothweiler, Lena Goetz, Philipp Diehl, Andreas Zirlik, Martin MoserAbstract:Objective— In addition to lowering cholesterol, statins exert pleiotropic effects on Endothelial Cells. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMP Endothelial Cell Precursor–derived regulator (BMPER), a novel member of the BMP pathway. Methods and Results— Mevastatin enhanced BMPER expression in cultured Endothelial Cells in a time- and concentration-dependent manner as determined by immunocytochemistry, RT-PCR, and Western blotting. Similar effects were observed in vitro and in vivo using simvastatin. Actinomycin D chase analysis and BMPER promoter reporter assays revealed that this is mostly a posttranscriptional event resulting in prolonged BMPER RNA half-life. We confirmed that the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase (Rock)/actin pathway is involved using the specific pathway activator cytotoxic necrotizing factor of Y ersinia pseudotuberculosis , which prevented upregulation of BMPER expression by mevastatin and pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, and cytochalasin D) that enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in Endothelial Cells as reflected by interCellular adhesion molecule–1 downregulation. Accordingly, silencing of BMPER enhances interCellular adhesion molecule–1 expression. Furthermore, mevastatin reduced the expression of proinflammatory BMP4, a well-known direct interaction partner of BMPER. Conclusion— Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rock/actin pathway, as well as by reducing BMP4 expression. BMP4 downregulation and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins.
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BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis
Circulation Research, 2008Co-Authors: Jennifer Heinke, Christoph Zoeller, Leonie Wehofsits, Kim Miriam Baar, Anna M. Laib, Thomas Helbing, Hellmut G Augustin, Christoph Bode, Qian Zhou, W. Cam PattersonAbstract:Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP Endothelial Cell Precursor–derived regulator) is a differentially expressed protein in embryonic Endothelial Precursor Cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on Endothelial Cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extraCellular matrix protein expressed by Endothelial Cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on Endothelial Cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from Endothelial Cells, sprouting is impaired. In terms of BMPER related intraCellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in Endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent Endothelial Cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis.
Cam Patterson - One of the best experts on this subject based on the ideXlab platform.
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Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Jennifer S. Esser, Christoph Bode, Cam Patterson, S. Rahner, Meike Deckler, Martin MoserAbstract: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-...
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BMPER-induced BMP signaling promotes coronary artery remodeling.
Developmental biology, 2013Co-Authors: Laura A. Dyer, Martin Moser, Cam PattersonAbstract:The connection of the coronary vasculature to the aorta is one of the last essential steps of cardiac development. However, little is known about the signaling events that promote normal coronary artery formation. The bone morphogenetic protein (BMP) signaling pathway regulates multiple aspects of Endothelial Cell biology but has not been specifically implicated in coronary vascular development. BMP signaling is tightly regulated by numerous factors, including BMP-binding Endothelial Cell Precursor-derived regulator (BMPER), which can both promote and repress BMP signaling activity. In the embryonic heart, BMPER expression is limited to the Endothelial Cells and the Endothelial-derived cushions, suggesting that BMPER may play a role in coronary vascular development. Histological analysis of BMPER(-/-) embryos at early embryonic stages demonstrates that commencement of coronary plexus differentiation is normal and that Endothelial apoptosis and Cell proliferation are unaffected in BMPER(-/-) embryos compared with wild-type embryos. However, analysis between embryonic days 15.5-17.5 reveals that, in BMPER(-/-) embryos, coronary arteries are either atretic or connected distal to the semilunar valves. In vitro tubulogenesis assays indicate that isolated BMPER(-/-) Endothelial Cells have impaired tube formation and migratory ability compared with wild-type Endothelial Cells, suggesting that these defects may lead to the observed coronary artery anomalies seen in BMPER(-/-) embryos. Additionally, recombinant BMPER promotes wild-type ventricular Endothelial migration in a dose-dependent manner, with a low concentration promoting and high concentrations inhibiting migration. Together, these results indicate that BMPER-regulated BMP signaling is critical for coronary plexus remodeling and normal coronary artery development.
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Antagonism and synergy between extraCellular BMP modulators Tsg and BMPER balance blood vessel formation
Journal of Cell Science, 2013Co-Authors: Jennifer Heinke, Thomas Helbing, Christoph Bode, Cam Patterson, Maria Juschkat, Anne Charlet, Leonie Mnich, Martin MoserAbstract:Summary Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extraCellular BMP modulators such as BMP Endothelial Cell Precursor derived regulator (BMPER), which we reported previously acts proangiogenically on Endothelial Cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on Endothelial Cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein Endothelial Cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on Endothelial Cells. Tsg enhanced Endothelial Cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro , dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular Cell homeostasis.
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BMPER Is Upregulated by Statins and Modulates Endothelial Inflammation by InterCellular Adhesion Molecule–1
Arteriosclerosis thrombosis and vascular biology, 2009Co-Authors: Thomas Helbing, Jennifer Heinke, Christoph Bode, Cam Patterson, Rene Rothweiler, Lena Goetz, Philipp Diehl, Andreas Zirlik, Martin MoserAbstract:Objective— In addition to lowering cholesterol, statins exert pleiotropic effects on Endothelial Cells. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMP Endothelial Cell Precursor–derived regulator (BMPER), a novel member of the BMP pathway. Methods and Results— Mevastatin enhanced BMPER expression in cultured Endothelial Cells in a time- and concentration-dependent manner as determined by immunocytochemistry, RT-PCR, and Western blotting. Similar effects were observed in vitro and in vivo using simvastatin. Actinomycin D chase analysis and BMPER promoter reporter assays revealed that this is mostly a posttranscriptional event resulting in prolonged BMPER RNA half-life. We confirmed that the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase (Rock)/actin pathway is involved using the specific pathway activator cytotoxic necrotizing factor of Y ersinia pseudotuberculosis , which prevented upregulation of BMPER expression by mevastatin and pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, and cytochalasin D) that enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in Endothelial Cells as reflected by interCellular adhesion molecule–1 downregulation. Accordingly, silencing of BMPER enhances interCellular adhesion molecule–1 expression. Furthermore, mevastatin reduced the expression of proinflammatory BMP4, a well-known direct interaction partner of BMPER. Conclusion— Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rock/actin pathway, as well as by reducing BMP4 expression. BMP4 downregulation and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins.
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BMPER is a conserved regulator of hematopoietic and vascular development in zebrafish
Journal of molecular and cellular cardiology, 2007Co-Authors: Martin Moser, Christoph Bode, Jing-wei Xiong, Cam PattersonAbstract:For the proper development of vertebrate embryos as well as for survival of the adult organism, it is essential to form a functional vascular system. Molecules involved in this process are members of highly conserved families of proteins that exert conserved functions across species. Bone morphogenetic proteins (BMP) are extraCellular factors that are regulated by extraCellular modulators and bind to BMP receptors, which in turn activate intraCellular signaling cascades. BMPs are necessary not only for induction of Endothelial and hematopoietic lineages but also for further Endothelial and hematopoietic Cell differentiation. Previously, we identified BMPER (BMP Endothelial Cell Precursor derived regulator) and demonstrated its spatiotemporal expression at sites of vasculogenesis and direct modulation of BMP activity. To directly investigate the role of BMPER in vascular development, we cloned the BMPER ortholog in zebrafish (zbmper). It is expressed at sites of high BMP activity, including vascular Precursor Cells located in the aortic arches and the intermediate Cell mass during zebrafish embryonic development. Knockdown of zbmper results in a dorsalized phenotype, a reduced number of gata1 expressing hematopoietic Precursor Cells and of circulating blood Cells as well as in a vascular phenotype. The generation of the caudal vein is compromised and the pattern guiding of the intersomitic vessels is disturbed, indicating that zbmper is required for early steps in vascular pattern formation and hematopoiesis in zebrafish.
W. Cam Patterson - One of the best experts on this subject based on the ideXlab platform.
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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
Arteriosclerosis thrombosis and vascular biology, 2011Co-Authors: Isabel Moreno-miralles, Rongqin Ren, Martin Moser, M.e. Hartnett, W. Cam PattersonAbstract:Objective—Bone morphogenetic proteins (BMPs) are potently proangiogenic; however, the mechanisms underlying the regulation of vessel development by BMPs are not fully understood. To assess the significance of BMP Endothelial Cell Precursor-derived regulator (BMPER) in blood vessel formation in vivo, we investigated its role in retinal angiogenesis. Methods and Results—In a model of oxygen-induced retinopathy, Bmper mRNA expression and protein levels are downregulated, correlating with the initiation of Sma and Mad related protein phosphorylation in Endothelial Cells. Moreover, Bmper haploinsufficiency results in an increased rate of retinal revascularization, with retinas from Bmper+/− mice displaying increased numbers of branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Furthermore, although Bmper haploinsufficiency does not alter Bmp expression, it does lead to an increase in BMP signaling, as evidenced by increased phosphorylated Sma and Mad related protein le...
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BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis
Circulation Research, 2008Co-Authors: Jennifer Heinke, Christoph Zoeller, Leonie Wehofsits, Kim Miriam Baar, Anna M. Laib, Thomas Helbing, Hellmut G Augustin, Christoph Bode, Qian Zhou, W. Cam PattersonAbstract:Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP Endothelial Cell Precursor–derived regulator) is a differentially expressed protein in embryonic Endothelial Precursor Cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on Endothelial Cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extraCellular matrix protein expressed by Endothelial Cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on Endothelial Cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from Endothelial Cells, sprouting is impaired. In terms of BMPER related intraCellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in Endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent Endothelial Cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis.
Jennifer Heinke - One of the best experts on this subject based on the ideXlab platform.
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Antagonism and synergy between extraCellular BMP modulators Tsg and BMPER balance blood vessel formation
Journal of Cell Science, 2013Co-Authors: Jennifer Heinke, Thomas Helbing, Christoph Bode, Cam Patterson, Maria Juschkat, Anne Charlet, Leonie Mnich, Martin MoserAbstract:Summary Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extraCellular BMP modulators such as BMP Endothelial Cell Precursor derived regulator (BMPER), which we reported previously acts proangiogenically on Endothelial Cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on Endothelial Cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein Endothelial Cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on Endothelial Cells. Tsg enhanced Endothelial Cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro , dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular Cell homeostasis.
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Bone morphogenetic protein modulator BMPER is highly expressed in malignant tumors and controls invasive Cell behavior
Oncogene, 2012Co-Authors: Jennifer Heinke, S. Rahner, M Kerber, L Mnich, S Lassmann, T Helbing, M Werner, C Patterson, C Bode, M MoserAbstract:Bone morphogenetic proteins (BMPs) are growth factors that exert important functions in Cell proliferation, migration and differentiation. Till date, multiple human tumors have been reported to display a dysregulation of several members of the BMP pathway that is associated with enhanced malignant tumor growth and metastasis. BMPER (BMP Endothelial Cell Precursor-derived regulator) is a direct BMP modulator that is necessary for BMPs to exert their full-range signaling activity. Moreover, BMPER is expressed by Endothelial Cells and their progenitors, and has pro-angiogenic features in these Cells. Here, we describe the expression of BMPER in human specimens of lung, colon and cervix carcinomas and Cell lines derived from such carcinomas. In contrast to healthy tissues, BMPER is highly expressed upon malignant deterioration. Functionally, loss of BMPER in the lung tumor Cell line A549 impairs proliferation, migration, invasion as well as tumor Cell-induced Endothelial Cell sprout formation. In contrast, stimulation of A549 Cells with exogenous BMPER had no further effect. We found that the BMPER effect may be transduced by regulation of the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 9 and 2. These facilitators of Cell migration are downregulated when BMPER is absent. To prove the relevance of our in vitro results in vivo , we generated Lewis lung carcinoma Cells with impaired BMPER expression and implanted them into the lungs of C57BL/6 mice. In this model, the absence of BMPER resulted in severely reduced tumor growth and tumor angiogenesis. Taken together, these data unequivocally demonstrate that the BMP modulator BMPER is highly expressed in malignant tumors and tumor growth is dependent on the presence of BMPER.
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BMPER Is Upregulated by Statins and Modulates Endothelial Inflammation by InterCellular Adhesion Molecule–1
Arteriosclerosis thrombosis and vascular biology, 2009Co-Authors: Thomas Helbing, Jennifer Heinke, Christoph Bode, Cam Patterson, Rene Rothweiler, Lena Goetz, Philipp Diehl, Andreas Zirlik, Martin MoserAbstract:Objective— In addition to lowering cholesterol, statins exert pleiotropic effects on Endothelial Cells. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMP Endothelial Cell Precursor–derived regulator (BMPER), a novel member of the BMP pathway. Methods and Results— Mevastatin enhanced BMPER expression in cultured Endothelial Cells in a time- and concentration-dependent manner as determined by immunocytochemistry, RT-PCR, and Western blotting. Similar effects were observed in vitro and in vivo using simvastatin. Actinomycin D chase analysis and BMPER promoter reporter assays revealed that this is mostly a posttranscriptional event resulting in prolonged BMPER RNA half-life. We confirmed that the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase (Rock)/actin pathway is involved using the specific pathway activator cytotoxic necrotizing factor of Y ersinia pseudotuberculosis , which prevented upregulation of BMPER expression by mevastatin and pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, and cytochalasin D) that enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in Endothelial Cells as reflected by interCellular adhesion molecule–1 downregulation. Accordingly, silencing of BMPER enhances interCellular adhesion molecule–1 expression. Furthermore, mevastatin reduced the expression of proinflammatory BMP4, a well-known direct interaction partner of BMPER. Conclusion— Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rock/actin pathway, as well as by reducing BMP4 expression. BMP4 downregulation and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins.
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BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis
Circulation Research, 2008Co-Authors: Jennifer Heinke, Christoph Zoeller, Leonie Wehofsits, Kim Miriam Baar, Anna M. Laib, Thomas Helbing, Hellmut G Augustin, Christoph Bode, Qian Zhou, W. Cam PattersonAbstract:Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP Endothelial Cell Precursor–derived regulator) is a differentially expressed protein in embryonic Endothelial Precursor Cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on Endothelial Cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extraCellular matrix protein expressed by Endothelial Cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on Endothelial Cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from Endothelial Cells, sprouting is impaired. In terms of BMPER related intraCellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in Endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent Endothelial Cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis.