scholarly journals Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells

2020 ◽  
Vol 133 (14) ◽  
pp. jcs239715 ◽  
Author(s):  
Paul D. Upton ◽  
John E. S. Park ◽  
Patricia M. De Souza ◽  
Rachel J. Davies ◽  
Mark J. D. Griffiths ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Endothelial Permeability ◽  
Type I ◽  
Type Ii ◽  
Morphogenetic Protein ◽  
Ccl2 Expression ◽  
Bone Morphogenetic Protein 9 ◽  
Macrophage Chemotaxis ◽  
Human Pulmonary Artery ◽  
Endothelial Integrity

ABSTRACTBone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte–macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.

scholarly journals Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher Agnew ◽  
Pelin Ayaz ◽  
Risa Kashima ◽  
Hanna S. Loving ◽  
Prajakta Ghatpande ◽  
...  
Keyword(s):  
Md Simulations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Exchange Mass Spectrometry ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

Abstract 17388: Loss of Bone Morphogenetic Protein 9 (BMP9) Limits Survival and Paradoxically Increases Collagen Abundance, but Limits Collagen Cross-Linking in a Murine Model of Acute Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shreyas Bhave ◽  
Michele Esposito ◽  
Lija Swain ◽  
Xiaoying QIAO ◽  
Gregory Martin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Morphogenetic Protein ◽  
Murine Model ◽  
Cardiac Remodeling ◽  
Type I Collagen ◽  
Cross Linking ◽  
Type I ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 9 ◽  
Collagen Cross Linking

Myocardial infarction (MI) is a major cause of heart failure (HF). HF is associated with adverse cardiac remodeling that is primarily driven by Transforming growth factor beta (TGFb1) mediated fibrosis and myocyte hypertrophy. We previously reported that loss of bone morphogenetic protein 9 (BMP9) promotes cardiac fibrosis in pressure-overload induced HF. No studies have explored a role for BMP9 in post MI cardiac remodeling. We hypothesize that loss of BMP9 may promote cardiac healing by stabilizing LV scar formation. To test this hypothesis, we subjected whole body BMP9 knockout (-/-) mice to left coronary artery ligation for two weeks followed by PV loop analysis and studied indices of cardiac remodeling. Compared to wild type (WT) controls BMP9-/- mice had significantly lower survival (83% vs 61%, p<0.001, respectively) with a higher rate of cardiac rupture(15% vs 90%). Compared to WT controls, surviving BMP9-/- mice had higher LVEDP, reduced LV dP/dt, and higher lung weight. Compared to WT mice, BMP9-/- mice had significantly higher levels of Type I collagen (2 fold p<0.05). Compared to WT mice, BMP9-/- mice had increased matrix metalloproteinases (MMP)-2 and MMP-9 (2.5 fold p<0.05) activity levels in the LV. Treatment of cultured primary human cardiac fibroblasts with recombinant BMP9 attenuated TGFb1-mediated Type I collagen and MMP-9 protein expression. To assess collagen content and cross-linking, two-photon excitation fluorescence imaging was performed and identified an increase in collagen abundance, but a trend towards lower collagen cross-linking in the LV of BMP9-/- mice compared to WT mice 2 weeks after MI. Our central finding is that loss of BMP9 is associated with reduced survival, increased propensity towards cardiac rupture, and increased LV collagen abundance, but reduced collagen integrity in a murine model of acute MI. These identify a potentially important functional role for BMP9 in post-infarct cardiac remodeling.

Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

1999 ◽  
Vol 112 (20) ◽  
pp. 3519-3527 ◽  
Author(s):  
T. Ebisawa ◽  
K. Tada ◽  
I. Kitajima ◽  
K. Tojo ◽  
T.K. Sampath ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Transforming Growth Factor ◽  
C2c12 Cells ◽  
Nuclear Accumulation ◽  
Type I ◽  
Type Ii ◽  
Weakly Bound ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Bone morphogenetic protein (BMP)-6 is a member of the transforming growth factor (TGF)-(β) superfamily, and is most similar to BMP-5, osteogenic protein (OP)-1/BMP-7, and OP-2/BMP-8. In the present study, we characterized the endogenous BMP-6 signaling pathway during osteoblast differentiation. BMP-6 strongly induced alkaline phosphatase (ALP) activity in cells of osteoblast lineage, including C2C12 cells, MC3T3-E1 cells, and ROB-C26 cells. The profile of binding of BMP-6 to type I and type II receptors was similar to that of OP-1/BMP-7 in C2C12 cells and MC3T3-E1 cells; BMP-6 strongly bound to activin receptor-like kinase (ALK)-2 (also termed ActR-I), together with type II receptors, i.e. BMP type II receptor (BMPR-II) and activin type II receptor (ActR-II). In addition, BMP-6 weakly bound to BMPR-IA (ALK-3), to which BMP-2 also bound. In contrast, binding of BMP-6 to BMPR-IB (ALK-6), and less efficiently to ALK-2 and BMPR-IA, together with BMPR-II was detected in ROB-C26 cells. Intracellular signalling was further studied using C2C12 and MC3T3-E1 cells. Among the receptor-regulated Smads activated by BMP receptors, BMP-6 strongly induced phosphorylation and nuclear accumulation of Smad5, and less efficiently those of Smad1. However, Smad8 was constitutively phosphorylated, and no further phosphorylation or nuclear accumulation of Smad8 by BMP-6 was observed. These findings indicate that in the process of differentiation to osteoblasts, BMP-6 binds to ALK-2 as well as other type I receptors, and transduces signals mainly through Smad5 and possibly through Smad1.

scholarly journals Regulation of the ALK1 ligands, BMP9 and BMP10

2016 ◽  
Vol 44 (4) ◽  
pp. 1135-1141 ◽  
Author(s):  
Wei Li ◽  
Richard M. Salmon ◽  
He Jiang ◽  
Nicholas W. Morrell
Keyword(s):  
Vascular Endothelial Cells ◽  
Type I ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Essential Information ◽  
Affinity Ligands ◽  
Protein Levels ◽  
Phase Ii Clinical Trials ◽  
Morphogenetic Protein ◽  
Genes Encoding ◽  
Pulmonary Arterial

Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies.

scholarly journals miR-10b Deficiency Affords Atherosclerosis Resistance

2018 ◽  
Author(s):  
Masako Nakahara ◽  
Norihiko Kobayashi ◽  
Masako Oka ◽  
Kenta Nakano ◽  
Tadashi Okamura ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Transforming Growth Factor Β ◽  
Experimental Atherosclerosis ◽  
High Cholesterol Diet ◽  
Type I ◽  
Type Ii ◽  
Protein Signaling ◽  
Leading Role ◽  
Growth Inhibitory

AbstractHuman vascular endothelial cells (ECs) are categorized into two groups; pro-stenotic (Type-I) and anti-stenotic (Type-II) ECs, and one of the master genes for a stress-induced “Type-II-to-Type-I” degeneration is Regulator of G-protein signaling 5 (RGS5). Here we show that miR-10b is a crucial downstream mediator in RGS5-dependent degeneration. We also demonstrated the miR-10bhigh Type-I EC exosome has a trans effect which suppresses anti-proliferative abilities of Type-II ECs. Moreover, we found miR-10b-deficient mice showed a resistance to experimental atherosclerosis, where high-fat-high-cholesterol-diet-fed mice were subjected to partial carotid ligation. Furthermore, we determined the key target of miR-10b was Latent transforming growth factor-β binding protein 1 (LTBP1), which is a regulator of TGF-β signaling. Compatible with a commonly accepted view that TGF-β creates the major growth-inhibitory signal against vascular smooth muscle cells, TGF-β inhibitor treatments abolished anti-proliferative functions of Type-II ECs. Therefore, RGS5/miR-10b/LTBP1/TGF-β axis plays a leading role in quality control of ECs.

Expression of Nitric Oxide Synthases in Nasal Mucosa from a Mouse Model of Allergic Rhinitis

2003 ◽  
Vol 112 (10) ◽  
pp. 899-903 ◽  
Author(s):  
Seung Jun Oh ◽  
Yang-Gi Min ◽  
Seung-Ju Lee ◽  
Jeong-Whun Kim ◽  
Peter R. Jarin
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Allergic Rhinitis ◽  
Nasal Mucosa ◽  
Vascular Endothelial Cells ◽  
Allergic Sensitization ◽  
Type I ◽  
Nasal Allergy ◽  
Vascular Endothelial ◽  
Type Ii

Nitric oxide (NO), which is produced by nitric oxide synthase (NOS), has been recently identified as a multifunctional mediator. As for nasal tissue, however, the distribution and expression patterns of 3 isoforms of NOS, including neuronal NOS (nNOS, type I NOS), inducible NOS (iNOS, type II NOS), and endothelial NOS (eNOS, type III NOS), are still unclear. To evaluate the function of NO in the pathophysiology of nasal allergy, we investigated the distribution of NOSs in the nasal mucosa of C57BL/6 mice with allergic rhinitis to the house dust mite, Dermatophagoides farinae. Immunoreactivity to each isoform of NOS was immunohisto-chemically observed. In the allergic nasal mucosa, many eosinophils had infiltrated. Immunoreactivity to NOS types I and III was localized to the surface epithelial and vascular endothelial cells in both allergic and control groups without a statistically significant difference. In contrast, the type II NOS immunoreactivity was weak in normal mice and increased after allergic sensitization. The type II NOS expression of the surface epithelial and vascular endothelial cells was significantly elevated in the allergic group as compared with the control group. These findings suggest that a large amount of NO may be produced in the nasal mucosa of mice by type II NOS after allergic sensitization and that type II NOS may play an important role in the pathogenesis of allergic rhinitis.

scholarly journals Differential Regulation of the Two Principal Runx2/Cbfa1 N-Terminal Isoforms in Response to Bone Morphogenetic Protein-2 during Development of the Osteoblast Phenotype

Endocrinology ◽  
2001 ◽  
Vol 142 (9) ◽  
pp. 4026-4039 ◽  
Author(s):  
Chaitali Banerjee ◽  
Amjad Javed ◽  
Je-Yong Choi ◽  
Jack Green ◽  
Vicki Rosen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Mesenchymal Cell ◽  
Cellular Protein ◽  
C2c12 Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Type Ii ◽  
Specific Expression ◽  
Morphogenetic Protein

Abstract Cbfa1/Runx2 is a transcription factor essential for bone formation and osteoblast differentiation. Two major N-terminal isoforms of Cbfa1, designated type I/p56 (PEBP2aA1, starting with the sequence MRIPV) and type II/p57 (til-1, starting with the sequence MASNS), each regulated by distinct promoters, are known. Here, we show that the type I transcript is constitutively expressed in nonosseous mesenchymal tissues and in osteoblast progenitor cells. Cbfa1 type I isoform expression does not change with the differentiation status of the cells. In contrast, the type II transcript is increased during differentiation of primary osteoblasts and is induced in osteoprogenitors and in premyoblast C2C12 cells in response to bone morphogenetic protein-2. The functional equivalence of the two isoforms in activation and repression of bone-specific genes indicates overlapping functional roles. The presence of the ubiquitous type I isoform in nonosseous cells and before bone morphogenetic protein-2 induced expression of the type II isoform suggests a regulatory role for Cbfa1 type I in early stages of mesenchymal cell development, whereas type II is necessary for osteogenesis and maintenance of the osteoblast phenotype. Our data indicate that Cbfa1 function is regulated by transcription, cellular protein levels, and DNA binding activity during osteoblast differentiation. Taken together, our studies suggest that developmental timing and cell type- specific expression of type I and type II Cbfa isoforms, and not necessarily molecular properties or sequences that reside in the N-terminus of Cbfa1, are the principal determinants of the osteogenic activity of Cbfa1.

scholarly journals Structure of bone morphogenetic protein 9 procomplex

2015 ◽  
Vol 112 (12) ◽  
pp. 3710-3715 ◽  
Author(s):  
Li-Zhi Mi ◽  
Christopher T. Brown ◽  
Yijie Gao ◽  
Yuan Tian ◽  
Viet Q. Le ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Sequence Conservation ◽  
Type I ◽  
Morphogenetic Protein ◽  
The Matrix ◽  
Bone Morphogenetic Protein 9 ◽  
Small Growth ◽  
Tgf Β1

Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro-BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N- and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both cross-armed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.

Therapeutic Mechanism of Chinese Medicine on the Healing of Early and Middle Fractures in Rabbits Under the Expression Level of Bone Morphogenetic Protein-2 (BMP-2) in Bone Tissue

2022 ◽  
Vol 12 (1) ◽  
pp. 45-51
Author(s):  
Hegui Xu ◽  
Yang Liu ◽  
Yuxiong Li ◽  
Wenbing Luo ◽  
Zhenyang Liu ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Bone Morphogenetic Protein ◽  
Expression Level ◽  
Bone Morphogenetic Protein 2 ◽  
Bone Collagen ◽  
Control Group ◽  
Type I ◽  
Type Ii ◽  
Morphogenetic Protein ◽  
Therapeutic Mechanism

In order to explore the therapeutic mechanism of Chinese medicine on the healing of rabbits early and middle fractures, a rabbit fracture model was established in this study. The study was divided into several groups, i.e., treatment group (TG) (fed with Chinese medicine Capsule) and control group (CG) (fed with normal saline (NS)). The materials were collected at 1, 3, and 5 weeks after the start of the experiment for analysis. The experiment content included: callus Hematoxylin-Eosin staining (HE staining); Bone Morphogenetic protein-2 (BMP-2) protein level detection; Type I and type II bone collagen (BC) detection; and serum biochemical factors detection. The experimental results showed that the formation of callus in the TG was better than in the CG; the BMP-2 protein expression level in the TG was higher than in the CG, and there were statistically significant differences (SSDs); the type I and type II BC levels in the TG were higher than the CG, there were SSDs; the levels of serum calcium (SC), phosphorus ion (PI), and alkaline phosphatase (ALP) in the TG were also higher than in the CG, and there were SSDs.

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