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      Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension

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          Abstract

          Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor–B (PDGF-B) induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH, and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA was upregulated in mice, and LysM‑Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, hypoxia-inducible factor 2a, or Pdgfb had reduced macrophage Pdgfb and were protected against distal muscularization and PH. Conversely, LysM‑Cre von-Hippel Lindau fl/fl mice had increased macrophage Hifa and Pdgfb and developed distal muscularization, PH, and RVH in normoxia. Similarly, Pdgfb was upregulated in macrophages from human idiopathic or systemic sclerosis–induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increased SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduced lung macrophage Pdgfb and prevented hypoxia-induced distal muscularization, PH, and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.

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          Most cited references67

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          2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).

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            Haemodynamic definitions and updated clinical classification of pulmonary hypertension

            Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management. Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to the specific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.
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              A global double-fluorescent Cre reporter mouse.

              The Cre/loxP system has been used extensively for conditional mutagenesis in mice. Reporters of Cre activity are important for defining the spatial and temporal extent of Cre-mediated recombination. Here we describe mT/mG, a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer Tomato (mT) prior to Cre-mediated excision and membrane-targeted green fluorescent protein (mG) after excision. We show that reporter expression is nearly ubiquitous, allowing visualization of fluorescent markers in live and fixed samples of all tissues examined. We further demonstrate that mG labeling is Cre-dependent, complementary to mT at single cell resolution, and distinguishable by fluorescence-activated cell sorting. Both membrane-targeted markers outline cell morphology, highlight membrane structures, and permit visualization of fine cellular processes. In addition to serving as a global Cre reporter, the mT/mG mouse may also be used as a tool for lineage tracing, transplantation studies, and analysis of cell morphology in vivo.
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                Author and article information

                Contributors
                Journal
                JCI Insight
                JCI Insight
                JCI Insight
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                22 March 2021
                22 March 2021
                22 March 2021
                : 6
                : 6
                : e139067
                Affiliations
                [1 ]Yale Cardiovascular Research Center, Section of Cardiovascular Medicine,
                [2 ]Department of Genetics,
                [3 ]Department of Biomedical Engineering,
                [4 ]Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, and
                [5 ]Department of Pathology, Yale University, New Haven, Connecticut, USA.
                Author notes
                Address correspondence to: Daniel M. Greif, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut 06511, USA. Phone: 203.737.6118; Email: daniel.greif@ 123456yale.edu .
                Author information
                http://orcid.org/0000-0002-5272-580X
                http://orcid.org/0000-0001-5240-7978
                http://orcid.org/0000-0001-6211-4327
                http://orcid.org/0000-0002-2163-549X
                http://orcid.org/0000-0002-9842-3751
                Article
                139067
                10.1172/jci.insight.139067
                8026182
                33591958
                0ebe6eaa-113c-4ae8-8797-56b164a06db7
                © 2021 Ntokou et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 April 2020
                : 11 February 2021
                Funding
                Funded by: American Heart Association, https://doi.org/10.13039/100000968;
                Award ID: 19EIA34660321
                Funded by: Department of Army
                Award ID: W81XWH-18-1-0629
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R01HL125815
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R01HL133016
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R01HL142674
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R21NS088854
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R01EB00487
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: T32DK101019
                Funded by: March of Dimes Foundation, https://doi.org/10.13039/100000912;
                Award ID: #6-FY15-223
                Funded by: National Institutes of Health
                Award ID: R35HL150766
                Categories
                Research Article

                pulmonology,vascular biology,cardiovascular disease,hypoxia,macrophages

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