The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nicholas W Morrell - One of the best experts on this subject based on the ideXlab platform.
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loss of smad3 promotes Vascular Remodeling in pulmonary arterial hypertension via mrtf disinhibition
American Journal of Respiratory and Critical Care Medicine, 2018Co-Authors: Diana Zabini, Elise Granton, Maria Zena Miranda, Ulrike Weichelt, S Bonnet, Nicholas W Morrell, Kim A Connelly, Steeve Provencher, Bahil GhanimAbstract:Rationale: Vascular Remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of Vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung Vascular Remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH.Objectives: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression.Methods: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overe...
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inflammation growth factors and pulmonary Vascular Remodeling
Journal of the American College of Cardiology, 2009Co-Authors: Paul M Hassoun, Luc Mouthon, Joan Albert Barbera, Saadia Eddahibi, Sonia C Flores, Friedrich Grimminger, Peter Lloyd Jones, Michael L Maitland, Evangelos D Michelakis, Nicholas W MorrellAbstract:Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary Vascular Remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the Vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as Vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary Vascular Remodeling. Thus, the recognition of complex inflammatory disturbances in the Vascular Remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary Vascular Remodeling and the possibility of future targeted therapy.
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molecular and cellular basis of pulmonary Vascular Remodeling in pulmonary hypertension
Progress in Cardiovascular Diseases, 2002Co-Authors: Trina K Jeffery, Nicholas W MorrellAbstract:Clinical pulmonary hypertension is characterized by a sustained elevation in pulmonary arterial pressure. Pulmonary Vascular Remodeling involves structural changes in the normal architecture of the walls of pulmonary arteries. The process of Vascular Remodeling can occur as a primary response to injury, or stimulus such as hypoxia, within the resistance vessels of the lung. Alternatively, the changes seen in more proximal vessels may arise secondary to a sustained increase in intraVascular pressure. To withstand the chronic increase in intraluminal pressure, the vessel wall becomes thickened and stronger. This "armouring" of the vessel wall with extra-smooth muscle and extracellular matrix leads to a decrease in lumen diameter and reduced capacity for vasodilatation. This maladaptive response results in increased pulmonary Vascular resistance and consequently, sustained pulmonary hypertension. The process of pulmonary Vascular Remodeling involves all layers of the vessel wall and is complicated by the finding that cellular heterogeneity exists within the traditional compartments of the Vascular wall: intima, media, and adventitia. In addition, the developmental stage of the organism greatly modifies the response of the pulmonary circulation to injury. This review focuses on the latest advances in our knowledge of these processes as they relate to specific forms of pulmonary hypertension and particularly in the light of recent genetic studies that have identified specific pathways involved in the pathogenesis of severe pulmonary hypertension.
Charles A Hales - One of the best experts on this subject based on the ideXlab platform.
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hypoxia does neither stimulate pulmonary artery endothelial cell proliferation in mice and rats with pulmonary hypertension and Vascular Remodeling nor in human pulmonary artery endothelial cells
Journal of Vascular Research, 2011Co-Authors: Lunyin Yu, Charles A HalesAbstract:Background: Hypoxia results in pulmonary hypertension and Vascular Remodeling due to induction of pulmonary artery cell proliferation. Besides pulmonary artery smooth muscle cells, pulmonary artery endothelial cells (PAECs) are also involved in the development of pulmonary hypertension, but the effect of hypoxia on PAEC proliferation has not been completely understood. Methods: We investigated PAEC proliferation in mice and rats with hypoxia-induced pulmonary hypertension and Vascular Remodeling as well as in human PAECs under hypoxia. Results and Conclusion: We did not find significant PAEC proliferation in chronically hypoxic rats or mice. There was a slight decrease in proliferation in mice and rats with pulmonary hypertension and Vascular Remodeling. We also did not find significant human PAEC proliferation and cell cycle progression under different levels of oxygen (1, 2, 3, 5 and 10%) for one day, although the same conditions of hypoxia induced significant proliferation and cell cycle progression in pulmonary artery smooth muscle cells and pulmonary artery fibroblasts. Exposure to hypoxia for 7 days also did not increase PAEC proliferation. These results demonstrated that hypoxia alone is not a stimulus to PAEC proliferation in vivo and in vitro. The present study provides a novel role for PAECs in hypoxia-induced pulmonary hypertension and Vascular Remodeling.
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effect of chemokine receptor cxcr4 on hypoxia induced pulmonary hypertension and Vascular Remodeling in rats
Respiratory Research, 2011Co-Authors: Charles A HalesAbstract:Background CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic Vascular repair and Remodeling, but the role of CXCR4 in development of pulmonary hypertension and Vascular Remodeling has not been fully understood.
Konstantin G Birukov - One of the best experts on this subject based on the ideXlab platform.
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cyclic stretch reactive oxygen species and Vascular Remodeling
Antioxidants & Redox Signaling, 2009Co-Authors: Konstantin G BirukovAbstract:Blood vessels respond to changes in mechanical load from circulating blood in the form of shear stress and mechanical strain as the result of heart propulsions by changes in intracellular signaling leading to changes in Vascular tone, production of vasoactive molecules, and changes in Vascular permeability, gene regulation, and Vascular Remodeling. In addition to hemodynamic forces, microvasculature in the lung is also exposed to stretch resulting from respiratory cycles during autonomous breathing or mechanical ventilation. Among various cell signaling pathways induced by mechanical forces and reported to date, a role of reactive oxygen species (ROS) produced by Vascular cells receives increasing attention. ROS play an essential role in signal transduction and physiologic regulation of Vascular function. However, in the settings of chronic hypertension, inflammation, or acute injury, ROS may trigger signaling events that further exacerbate smooth muscle hypercontractility and Vascular Remodeling associated with hypertension and endothelial barrier dysfunction associated with acute lung injury and pulmonary edema. These conditions are also characterized by altered patterns of mechanical stimulation experienced by vasculature. This review will discuss signaling pathways regulated by ROS and mechanical stretch in the pulmonary and systemic vasculature and will summarize functional interactions between cyclic stretch- and ROS-induced signaling in mechanochemical regulation of Vascular structure and function.
Bahil Ghanim - One of the best experts on this subject based on the ideXlab platform.
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loss of smad3 promotes Vascular Remodeling in pulmonary arterial hypertension via mrtf disinhibition
American Journal of Respiratory and Critical Care Medicine, 2018Co-Authors: Diana Zabini, Elise Granton, Maria Zena Miranda, Ulrike Weichelt, S Bonnet, Nicholas W Morrell, Kim A Connelly, Steeve Provencher, Bahil GhanimAbstract:Rationale: Vascular Remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of Vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung Vascular Remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH.Objectives: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression.Methods: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overe...
S Bonnet - One of the best experts on this subject based on the ideXlab platform.
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loss of smad3 promotes Vascular Remodeling in pulmonary arterial hypertension via mrtf disinhibition
American Journal of Respiratory and Critical Care Medicine, 2018Co-Authors: Diana Zabini, Elise Granton, Maria Zena Miranda, Ulrike Weichelt, S Bonnet, Nicholas W Morrell, Kim A Connelly, Steeve Provencher, Bahil GhanimAbstract:Rationale: Vascular Remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of Vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung Vascular Remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH.Objectives: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression.Methods: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overe...
