Inhibition of apelin expression by BMP signaling in endothelial cells

The transforming growth factor-β/bone morphogenic protein (BMP) system is a major pathway for angiogenesis and is involved in hereditary vascular diseases. Here we report that the gene encoding the vasoactive and vascular cell growth-regulating peptide apelin is a target of the BMP pathway. We demonstrate that apelin expression is strongly downregulated by BMP in an endothelial cell line as well as in lung endothelial microvascular cells. We show that BMP signals through the BMPR2-SMAD pathway to downregulate apelin expression and that a transcriptional direct and indirect mechanism is required. The BMP-induced downregulation of apelin expression was found to be critical for hypoxia-induced growth of endothelial cells, because the growth inhibitory effect of BMP in this condition is suppressed by enforced expression of apelin. Thus, we describe an important link between a signaling pathway involved in angiogenesis and vascular diseases and a peptide regulating vascular homeostasis.

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The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

International Journal of Molecular Sciences ◽

10.3390/ijms22126364 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6364

Author(s):

Ljuba C. Ponomarev ◽

Jakub Ksiazkiewicz ◽

Michael W. Staring ◽

Aernout Luttun ◽

An Zwijsen

Keyword(s):

Endothelial Cells ◽

Bone Morphogenetic Proteins ◽

Lymphatic Vessel ◽

Lymphatic Vessels ◽

Vascular Diseases ◽

Bmp Signaling ◽

Molecular Heterogeneity ◽

Active Components ◽

Surrounding Matrix ◽

Bmp Pathway

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.

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Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21113888 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3888

Author(s):

Sarah Ouahoud ◽

James C.H. Hardwick ◽

Lukas J.A.C. Hawinkels

Keyword(s):

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Biological Processes ◽

Adult Tissue ◽

Aberrant Expression ◽

Bmp Pathway ◽

Bmp Antagonists

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.

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The BMP Pathway and Its Inhibitors in the Skeleton

Physiological Reviews ◽

10.1152/physrev.00028.2017 ◽

2018 ◽

Vol 98 (4) ◽

pp. 2431-2452 ◽

Cited By ~ 37

Author(s):

Jonathan W. Lowery ◽

Vicki Rosen

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Transforming Growth Factor ◽

Bone Development ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Comprehensive Overview ◽

Organ Systems ◽

Bmp Pathway ◽

Gene Regulatory

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.

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Cytokine analysis in patients with different stages of thromboangiitis obliterans

Current Molecular Medicine ◽

10.2174/1566524020666201120112828 ◽

2020 ◽

Vol 20 ◽

Author(s):

Abbas Shapouri-Moghaddam ◽

Seyed Jalil Tavakkol Afshari ◽

Mohammad-Hadi Saeed Modaghegh ◽

Hamid Reza Rahimi ◽

Mahmoud Mahmoudi ◽

...

Keyword(s):

Transforming Growth Factor ◽

Vascular Diseases ◽

Transforming Growth Factor Β ◽

Serum Levels ◽

Interferon Γ ◽

Analysis Of Covariance ◽

Cold Sensitivity ◽

Thromboangiitis Obliterans ◽

Burning Pain ◽

Cytokine Analysis

Background: Studies suggest that cytokines are involved in the development of both inflammatory disorders and vascular diseases. Objective: The changes in transforming growth factor β (TGFβ), interleukin 6 (IL6), tumor necrosis factor α (TNFα), and interferon γ (IFNγ) with the progression of the thromboangiitis obliterans (TAO) symptomswereinvestigated in this research. Methods: This study included 80 patients with TAO, who were selected from the Vascular and Endovascular Research Center in Alavi Hospital between 2012 and 2016. They were then categorized into three groups: mild (migratory thrombophlebitis, cold sensitivity or Raynaud's phenomenon, and skin discoloration), moderate (chronic ulcers, claudication, and burning pain of the feet at night), and severe (pain at rest and spontaneous gangrene) symptoms. The serum levels of TGFβ, IL6, TNFα, and IFNγwere determinedby the ELISA method and compared among the groups. Results: The first three predominant symptoms were pulse disorder (n = 76, 95.00%), cold intolerance (n = 61, 76.25%), and claudication (n = 59, 73.75%). A comparison of the analysis of covariance (ANCOVA) revealed that both TGFβ and IL6 were dysregulatedas the severity of the symptoms increased from the moderate to the severe stages; however, such changes were not significant(p > 0.05). In the multiple logistic regression model, increased TNFαlevelswere seen in the presence of the moderatesymptoms as compared to the severe ones (p < 0.05). Conclusion: It could be concluded that TNFα, as part of the defining cytokine-production profile of Thelper cells, can be significantly involved in the progression of TAO from the moderate to the severe stages.

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EGR2, IGF1 and IL6 Expression Are Elevated in the Intervertebral Disc of Patients Suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH) Compared to Degenerative or Trauma Discs

Applied Sciences ◽

10.3390/app11094072 ◽

2021 ◽

Vol 11 (9) ◽

pp. 4072

Author(s):

Benjamin Gantenbein ◽

Rahel D. May ◽

Paola Bermudez-Lekerika ◽

Katharina A. C. Oswald ◽

Lorin M. Benneker ◽

...

Keyword(s):

Growth Factor ◽

Nucleus Pulposus ◽

Transforming Growth Factor ◽

Diffuse Idiopathic Skeletal Hyperostosis ◽

Transforming Growth Factor Β ◽

Intervertebral Discs ◽

Serum Marker ◽

Ectopic Ossification ◽

Disc Cells ◽

Bmp Pathway

Diffuse idiopathic skeletal hyperostosis (DISH) is characterised by ectopic ossification along the anterior spine and the outer intervertebral discs (IVD). However, the centre of the IVD, i.e., the nucleus pulposus, always remains unaffected, which could be due to the inhibition of the bone morphogenetic protein (BMP) pathway. In this study, we investigated the transcriptome for the BMP pathway of DISH-IVD cells versus disc cells of traumatic or degenerative discs. The disc cells originated from nucleus pulposus (NP), annulus fibrosus (AF) and from cartilaginous endplate (CEP) tissue. Here, ninety genes of the transforming growth factor β-BMP signalling pathway were screened by qPCR. Furthermore, the protein expression of genes of interest was further investigated by immune-staining and semi-quantitative microscopy. IVDs of three DISH patients were tested against three control patients (same disc level and similar age). Early Growth Response 2 (EGR2) and Interleukin 6 (IL6) were both significantly up-regulated in DISH-IVD cells compared to controls (12.8 ± 7.6-fold and 54.0 ± 46.5-fold, respectively, means ± SEM). Furthermore, Insulin-like Growth Factor 1 (IGF1) tended to be up-regulated in DISH-IVD donors, i.e., 174.13 ± 120.6-fold. IGF1 was already known as a serum marker for DISH and other rheumatoid diseases and is confirmed here to play a possible key role in DISH-IVD.

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GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916034117 ◽

2020 ◽

Vol 117 (9) ◽

pp. 4910-4920 ◽

Cited By ~ 3

Author(s):

Joonho Suh ◽

Na-Kyung Kim ◽

Seung-Hoon Lee ◽

Je-Hyun Eom ◽

Youngkyun Lee ◽

...

Keyword(s):

Bone Mass ◽

Muscle Mass ◽

Transforming Growth Factor ◽

Bone Fractures ◽

Muscle Growth ◽

Transforming Growth Factor Β ◽

Biochemical Properties ◽

Bmp Signaling ◽

Morphogenetic Protein ◽

Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

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Intracisternal administration of transforming growth factor-β evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00181.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. R266-R275 ◽

Cited By ~ 3

Author(s):

Shigenobu Matsumura ◽

Tetsuro Shibakusa ◽

Teppei Fujikawa ◽

Hiroyuki Yamada ◽

Kiyoshi Matsumura ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Proinflammatory Cytokines ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cyclooxygenase 2 ◽

Dependent Manner ◽

Cox 2 ◽

Β Receptor

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2 dependent. TGF-β increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.

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