scholarly journals ID family protein expression and regulation in hypoxic pulmonary hypertension

2010 ◽  
Vol 299 (6) ◽  
pp. R1463-R1477 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Andrea L. Frump ◽  
Lynda Anderson ◽  
Gabriella E. DiCarlo ◽  
Mark T. Jones ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Bmp Signaling ◽  
Mouse Lung ◽  
Ph Response ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
Morphogenetic Protein ◽  
Family Protein

Bone morphogenetic protein (BMP) signaling has been linked to the development of pulmonary hypertension (PH). Inhibitors of differentiation (ID) proteins (ID1–4) are a family of basic helix-loop-helix transcription factors that are downstream targets of the BMP signaling pathway, but the role that ID proteins play in the development of PH is unknown. To address this, we evaluated pulmonary expression of ID proteins in a mouse model of hypoxia-induced PH. There is selective induction of ID1 and ID3 expression in hypoxic pulmonary vascular smooth muscle cells (VSMCs) in vivo, and ID1 and ID3 expression are increased by hypoxia in cultured pulmonary VSMCs in a BMP-dependent fashion. ID4 protein is barely detectable in the mouse lung, and while ID2 is induced in hypoxic peripheral VSMCs in vivo, it is not increased by hypoxia or BMP signaling in cultured pulmonary VSMCs. In addition, the PH response to chronic hypoxia is indistinguishable between wild type and Id1 null mice. This is associated with a compensatory increase in ID3 but not ID2 expression in pulmonary VSMCs of Id1 null mice. These findings indicate that ID1 is dispensable for mounting a normal pulmonary vascular response to hypoxia, but suggest that ID3 may compensate for loss of ID1 expression in pulmonary VSMCs. Taken together, these findings indicate that ID1 and ID3 expression are regulated in a BMP-dependent fashion in hypoxic pulmonary VSMCs, and that ID1 and ID3 may play a cooperative role in regulating BMP-dependent VSMC responses to chronic hypoxia.

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4005-4015 ◽  
Author(s):  
M. Weaver ◽  
J.M. Yingling ◽  
N.R. Dunn ◽  
S. Bellusci ◽  
B.L. Hogan
Keyword(s):  
Cell Types ◽  
Surfactant Protein ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Clara Cell ◽  
Mouse Lung ◽  
Marker Genes ◽  
Distal Marker ◽  
Morphogenetic Protein

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693–1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension

2007 ◽  
Vol 292 (1) ◽  
pp. L154-L164 ◽  
Author(s):  
D. Case ◽  
D. Irwin ◽  
C. Ivester ◽  
J. Harral ◽  
K. Morris ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Left Ventricular ◽  
Wild Type ◽  
Ph Response ◽  
Subtractive Library

Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in the ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible β-galactoside-binding lectin produced by vascular, interstitial, epithelial, and immune cells. Gal-1 regulates SMC differentiation, proliferation, and apoptosis via interactions with the ECM, as well as immune system function, and, therefore, likely plays a role in the pathogenesis of PH. We investigated the effects of Gal-1 during hypoxic PH by quantifying 1) Gal-1 expression in response to hypoxia in vitro and in vivo and 2) the effect of Gal-1 gene deletion on the magnitude of the PH response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found that acute hypoxia increases expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells. In wild-type (WT) mice, Gal-1 immunoreactivity increased after 6 wk of hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1−/−) mice showed a decreased PH response, as measured by right ventricular pressure and the ratio of right ventricular to left ventricular + septum wet weight compared with their WT counterparts. However, the number and degree of muscularized vessels increased similarly in WT and Gal-1−/− mice. In response to chronic hypoxia, the decrease in factor 8-positive microvessel density was similar in both groups. Vasoreactivity of WT and Gal-1−/− mice was tested in vivo and with use of isolated perfused lungs exposed to acute hypoxia. Acute hypoxia caused a significant increase in RV pressure in wild-type and Gal-1−/− mice; however, the response of the Gal-1−/− mice was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hypoxia-induced PH, which influences disease progression.

scholarly journals A novel BR-SMAD is required for larval development in barber’s pole worm Haemonchus contortus

2021 ◽  
Vol 8 (2) ◽  
pp. 57-64
Author(s):  
Fangfang Li ◽  
Peixi Qin ◽  
Lisha Ye ◽  
Nishith Gupta ◽  
Min Hu
Keyword(s):  
Haemonchus Contortus ◽  
Developmental Stages ◽  
Small Ruminants ◽  
Bmp Signaling ◽  
Bimolecular Fluorescence Complementation ◽  
Blood Sucking ◽  
Morphogenetic Protein ◽  
Smad Proteins ◽  
Family Protein ◽  
Parasitic Worms

SMAD proteins mediate TGF-β signaling and thereby regulate the metazoan development; however, they are poorly defined in Haemonchus contortus–a common blood-sucking parasitic nematode of small ruminants. Here, we characterized an R-SMAD family protein in H. contortus termed HcSMA2, which is closely related to Caenorhabditis elegans SMA2 (CeSMA2) involved in the bone morphogenetic protein (BMP) signaling. Hcsma2 is transcribed in all developmental stages of H. contortus but highly induced in the adult male worms. The RNA interference with Hcsma2 retarded the transition of infective L3 into L4 larvae. Besides, the bimolecular fluorescence complementation revealed the interaction of HcSMA2 with a TGF-β-activated-R-SMAD (HcDAF8). Together these results show a BMP-like receptor-regulated SMAD in H. contortus that is required for larval differentiation and underscore an adaptive functional repurposing of BMP-signaling in parasitic worms.

scholarly journals Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension

2019 ◽  
Vol 244 (3) ◽  
pp. 252-261 ◽  
Author(s):  
Gexiang Cai ◽  
Jingjing Liu ◽  
Meibin Wang ◽  
Lihuang Su ◽  
Mengsi Cai ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Lung ◽  
Fibroblast Growth Factor 21 ◽  
Arterial Remodeling ◽  
Collagen Deposition ◽  
Pparγ Agonist ◽  
Pulmonary Arterial ◽  
The Relationship

Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPARγ in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPARγ agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPARγ in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPARγ in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPARγ levels. These changes were reversed by exogenous FGF21 and a PPARγ agonist and were further enhanced by a PPARγ antagonist. The hypoxia-induced decrease in β-klotho (KLB) expression was improved by the PPARγ agonist and further reduced by the PPARγ antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPARγ coactivator-1α (PGC-1α) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPARγ expression, and the PPARγ-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPARγ mutually promote each other’s expression in HPH via the AMPK/PGC-1α pathway and KLB protein. Impact statement In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other’s expression via the AMPK/PGC-1α pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

scholarly journals SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

2015 ◽  
Vol 35 (12) ◽  
pp. 2165-2172 ◽  
Author(s):  
Jonathon Marks-Bluth ◽  
Anchit Khanna ◽  
Vashe Chandrakanthan ◽  
Julie Thoms ◽  
Thomas Bee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Selective Advantage ◽  
Regulatory Elements ◽  
Bmp Signaling ◽  
Tissue Specific ◽  
Morphogenetic Protein ◽  
Smad Signaling Pathway ◽  
Endothelial Development

The bone morphogenetic protein (BMP)/SMAD signaling pathway is a critical regulator of angiogenic sprouting and is involved in vascular development in the embryo. SMAD1 and SMAD5, the core mediators of BMP signaling, are vital for this activity, yet little is known about their transcriptional regulation in endothelial cells. Here, we have integrated multispecies sequence conservation, tissue-specific chromatin,in vitroreporter assay, andin vivotransgenic data to identify and validateSmad1+63 and theSmad5promoter as tissue-specificcis-regulatory elements that are active in the developing endothelium. The activity of these elements in the endothelium was dependent on highly conserved ETS, GATA, and E-box motifs, and chromatin immunoprecipitation showed high levels of enrichment of FLI1, GATA2, and SCL at these sites in endothelial cell lines and E11 dorsal aortasin vivo. Knockdown of FLI1 and GATA2 but not SCL reduced the expression of SMAD1 and SMAD5 in endothelial cellsin vitro. In contrast, CD31+cKit−endothelial cells harvested from embryonic day 9 (E9) aorta-gonad-mesonephros (AGM) regions of GATA2 null embryos showed reducedSmad1but notSmad5transcript levels. This is suggestive of a degree ofin vivoselection where, in the case of reduced SMAD1 levels, endothelial cells with more robust SMAD5 expression have a selective advantage.

scholarly journals Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation

2010 ◽  
Vol 190 (6) ◽  
pp. 1107-1121 ◽  
Author(s):  
Harikiran Nistala ◽  
Sui Lee-Arteaga ◽  
Silvia Smaldone ◽  
Gabriella Siciliano ◽  
Luca Carta ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transforming Growth Factor ◽  
Bone Mineralization ◽  
Bmp Signaling ◽  
Direct Role ◽  
Morphogenetic Protein ◽  
Fibrillin 1 ◽  
Osteoblast Maturation

Extracellular regulation of signaling by transforming growth factor (TGF)–β family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-β and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2–null (Fbn2−/−) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2−/− phenotype is accounted for by improper activation of latent TGF-β that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1−/− mice exhibit improper latent TGF-β activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-β and BMP signaling.

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2657-2665 ◽  
Author(s):  
Katarzyna Mleczko-Sanecka ◽  
Guillem Casanovas ◽  
Anan Ragab ◽  
Katja Breitkopf ◽  
Alexandra Müller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Iron Metabolism ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Protein

Abstract Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.

scholarly journals Transcription factor Tcf4 is the preferred heterodimerization partner for Olig2 in oligodendrocytes and required for differentiation

2020 ◽  
Vol 48 (9) ◽  
pp. 4839-4857 ◽  
Author(s):  
Miriam Wedel ◽  
Franziska Fröb ◽  
Olga Elsesser ◽  
Marie-Theres Wittmann ◽  
D Chichung Lie ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Physical Interaction ◽  
Functional Studies ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Mouse Mutants ◽  
Id Proteins ◽  
A Cell ◽  
Oligodendrocyte Development

Abstract Development of oligodendrocytes and myelin formation in the vertebrate central nervous system is under control of several basic helix-loop-helix transcription factors such as Olig2, Ascl1, Hes5 and the Id proteins. The class I basic helix-loop-helix proteins Tcf3, Tcf4 and Tcf12 represent potential heterodimerization partners and functional modulators for all, but have not been investigated in oligodendrocytes so far. Using mouse mutants, organotypic slice and primary cell cultures we here show that Tcf4 is required in a cell-autonomous manner for proper terminal differentiation and myelination in vivo and ex vivo. Partial compensation is provided by the paralogous Tcf3, but not Tcf12. On the mechanistic level Tcf4 was identified as the preferred heterodimerization partner of the central regulator of oligodendrocyte development Olig2. Both genetic studies in the mouse as well as functional studies on enhancer regions of myelin genes confirmed the relevance of this physical interaction for oligodendrocyte differentiation. Considering that alterations in TCF4 are associated with syndromic and non-syndromic forms of intellectual disability, schizophrenia and autism in humans, our findings point to the possibility of an oligodendroglial contribution to these disorders.

Cellular adaptation during chronic neonatal hypoxic pulmonary hypertension

1991 ◽  
Vol 261 (4) ◽  
pp. L97-L104 ◽  
Author(s):  
Kurt R. Stenmark ◽  
Almas A. Aldashev ◽  
Ernest C. Orton ◽  
A. G. Durmowicz ◽  
D. B. Badesch ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Arterial Wall ◽  
Chronic Hypoxia ◽  
Left Pulmonary Artery ◽  
Right Atrial ◽  
Vascular Changes ◽  
Hypoxic Pulmonary Hypertension

Newbor animals develop more severe hypoxic pulmonary hypertension than do adults, their vascular changes are greater, and both the hypertension and vascular changes occur more rapidly. We hypothesize that this differential developmentally controlled response may arise from either a difference in the type or quantity of endogenously secreted mediators in response to a given injury or a difference in the replicative and/or matrix-producing response of the vascular cells to physical or chemical stimuli. We investigated the effect of chronic hypoxia (14 days) on the proliferative and matrix-producing phenotype of the neonatal (14-day-old) pulmonary artery smooth muscle cell (SMC) and examined the heterogeneity and potential mechanisms responsible for this response. In situ hybridization studies demonstrated a remarkable change in the distribution of cells hybridizing with a tropoelastin cRNA probe after 14 days of hypoxia. Studies also demonstrated a population of SMC that did not hybridize with the elastin or collagen probes, indicating that the pulmonary artery contains SMC of multiple phenotypes and that the response to hypoxic and hemodynamic stress is not uniform for the various types. Bromodeoxyuridine labeling experiments indicated a large increase in DNA synthesis in hypertensive vessels, which, again, was not uniform either across or along the arterial wall. In vitro experiments with neonatal SMC suggested that hypoxia alone could not be responsible for the proliferative or matrix changes. These observations were supported by in vivo experiments in which coarctation of the left pulmonary artery, which markedly decreased pressure and flow to the left lung in hypoxic animals (14 days), resulted in significant decreases in collagen and elastin message levels in the left pulmonary artery distal to the coarctation compared with location-matched vessels from the right lung. Finally, we noted marked decreases in B-receptor density and adenyl cyclase activity in right atrial and pulmonary artery tissue from the chronically hypoxic animals. Decreases in the ability of the cell to produce adenosine 3',5'-cyclic monophosphate could significantly affect both the proliferative and matrix-producing potential of the SMC. We conclude that in vivo adaptation of the pulmonary artery SMC to chronic hypoxia includes changes in protein synthesis, cell proliferation, receptor expression, and enzyme activity. Further, there is a marked heterogeneity of these responses both across and along the arterial wall. hypoxia; phenotype; signal transductions; smooth muscle cells

scholarly journals Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5037-5047 ◽  
Author(s):  
Yucheng Yao ◽  
Medet Jumabay ◽  
Albert Ly ◽  
Melina Radparvar ◽  
Anthony H. Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelium ◽  
Feedback Inhibition ◽  
Tube Formation ◽  
Bmp Signaling ◽  
Matrix Gla Protein ◽  
Morphogenetic Protein ◽  
Mutual Regulation ◽  
Bone Morphogenetic Protein 9

Abstract The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.

Sign in / Sign up

Export Citation Format

Share Document