Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 10, 2021

During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such development. Here, we use MULTI-seq generate scRNA-seq profiles over 66,000 cells from 36 mice normal or impaired secondary hyperoxia with validation some the findings lungs BPD patients. We observe dynamic populations cells, including several rare cell types putative progenitors. Hyperoxia exposure, which mimics phenotype, alters composition all compartments, particularly epithelium, stromal fibroblasts, capillary endothelium macrophage populations. Pathway analysis predicted crosstalk suggest inflammatory signaling main driver hyperoxia-induced changes. Our data provides a single-cell view changes associated health disease.

Язык: Английский

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Endothelial-Mesenchymal Transition in Cardiovascular Disease

Arteriosclerosis Thrombosis and Vascular Biology, Год журнала: 2021, Номер 41(9), С. 2357 - 2369

Опубликована: Июль 1, 2021

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent properties and take on mesenchymal cell behaviors. To begin the process, loosen their cell-cell junctions, degrade basement membrane, migrate out into perivascular surroundings. These initial behaviors reflect transient modulation of cellular phenotype, that is, phenotypic modulation, sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening junctions migration are also seen inflammatory angiogenic settings such initiating have overlapping gene expression with responding signals or sprouting form new blood vessels. Reduced increase permeability, facilitates leukocyte trafficking, whereas precedes neovascularization; both barriers quiescence restored stimuli subside. Complete proceeds beyond characteristics become prominent functions diminish. In proadaptive, regenerative produce extracellular matrix contribute tissue integrity maladaptive, pathologic fibrotic, overproducing cause stiffness, eventually impacts function. Here we will review what known about how TGF (transforming growth factor) β influences this continuum from junctional loosening its relevance cardiovascular diseases.

Язык: Английский

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Pathophysiology and new advances in pulmonary hypertension

BMJ Medicine, Год журнала: 2023, Номер 2(1), С. e000137 - e000137

Опубликована: Март 1, 2023

Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the circulation, formation of vaso-occlusive lesions. These lead to right ventricular afterload, which progresses maladaptive remodelling eventually death. represents one most severe best studied types consistently targeted drug treatments. The underlying molecular pathogenesis complex multifactorial process, but can be several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence sex hormones, abnormalities ventricle. Current treatments for some other target pathways involved control vascular tone proliferation; however, these have limited efficacy on patient outcomes. This review describes key features hypertension, discusses current emerging therapeutic interventions, points future directions research care. Because progress specialty has been made this focuses type hypertension. highlights pathophysiological concepts directions, targeting cellular metabolism, genetics epigenetics, hormone signalling, bone morphogenetic protein inhibition tyrosine kinase receptors.

Язык: Английский

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Vascular Inflammatory Diseases and Endothelial Phenotypes

Cells, Год журнала: 2023, Номер 12(12), С. 1640 - 1640

Опубликована: Июнь 15, 2023

The physiological functions of endothelial cells control vascular tone, permeability, inflammation, and angiogenesis, which significantly help to maintain a healthy system. Several cardiovascular diseases are characterized by cell activation or dysfunction triggered external stimuli such as disturbed flow, hypoxia, growth factors, cytokines in response high levels low-density lipoprotein cholesterol, hypertension, diabetes, aging, drugs, smoking. Increasing evidence suggests that uncontrolled proinflammatory signaling further alteration phenotypes barrier disruption, increased mesenchymal transition (EndMT), metabolic reprogramming induce diseases, multiple studies focusing on finding the pathways mechanisms involved it. This review highlights main their effects function. In order provide rational direction for future research, we also compiled most recent data regarding impact potential targets impede pathogenic process.

Язык: Английский

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Endothelial to mesenchymal transition: at the axis of cardiovascular health and disease

Cardiovascular Research, Год журнала: 2024, Номер 120(3), С. 223 - 236

Опубликована: Фев. 1, 2024

Abstract Endothelial cells (ECs) line the luminal surface of blood vessels and play a major role in vascular (patho)-physiology by acting as barrier, sensing circulating factors intrinsic/extrinsic signals. ECs have capacity to undergo endothelial-to-mesenchymal transition (EndMT), complex differentiation process with key roles both during embryonic development adulthood. EndMT can contribute EC activation dysfunctional alterations associated maladaptive tissue responses human disease. During EndMT, progressively changes leading expression mesenchymal markers while repressing lineage-specific traits. This phenotypic functional switch is considered largely exist continuum, being characterized gradation transitioning stages. In this report, we discuss plasticity potential reversibility hypothesis that different EndMT-derived cell populations may disease progression or resolution. addition, review advancements field, current technical challenges, well therapeutic options opportunities context cardiovascular biology.

Язык: Английский

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Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Biomedicines, Год журнала: 2021, Номер 9(1), С. 57 - 57

Опубликована: Янв. 9, 2021

Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that characterized by the abnormal remodeling of pulmonary arteries leads to right ventricular failure death. Although our understanding causes for vascular in PAH limited, accumulating evidence indicates endothelial cell (EC) dysfunction one first triggers initiating this process. EC activation several cellular signalling pathways endothelium, resulting uncontrolled proliferation ECs, artery smooth muscle cells, fibroblasts, eventually remodelling occlusion blood vessels. Other factors are related an increase mesenchymal transition, inflammation, apoptosis, thrombus formation. In review, we outline latest advances on role other forms hypertension. We also elaborate molecular signals orchestrate PAH. Understanding mechanisms will unravel therapeutic potential targeting process

Язык: Английский

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Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Май 12, 2022

Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling inflammatory immune responses prominently upregulated lungs a Sugen-hypoxia rat model severe angio-obliterative PAH, concordant profiles observed PAH patients. Therapeutic treatment ActRIIA-Fc-but not vasodilator-strikingly reversed proinflammatory proliferative gene normalized macrophage infiltration diseased rodent lungs. Furthermore, corrected structure Bmpr2 haploinsufficient mice subjected to hypoxia, heritable PAH. Three high-affinity ligands each induced activation vitro, their combined immunoneutralization rats produced benefits comparable those elicited ActRIIA-Fc. Our results complementary experimental genetic models reveal therapeutic anti-inflammatory activities that, together its known anti-proliferative effects on vascular cell types, could underlie clinical activity sotatercept as either monotherapy or add-on current therapies.

Язык: Английский

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The context-dependent, combinatorial logic of BMP signaling

Cell Systems, Год журнала: 2022, Номер 13(5), С. 388 - 407.e10

Опубликована: Апрель 13, 2022

Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way which ligands are presented extracellularly receptors expressed by signal-receiving cell. To understand combinatorial logic such a system, we systematically measured pairwise bone morphogenetic protein (BMP) interactions cells with varying expression. Ligands could be classified into equivalence groups based their profile positive negative synergies other ligands. These varied expression, explaining how can functionally replace each one context but not another. Context-dependent explained biochemical model competitive formation alternative signaling complexes distinct activities. Together, these results provide insights roles BMP combinations developmental therapeutic contexts establish framework for analyzing combinatorial, context-dependent systems.

Язык: Английский

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BMP9 and BMP10: Two close vascular quiescence partners that stand out

Developmental Dynamics, Год журнала: 2021, Номер 251(1), С. 158 - 177

Опубликована: Июль 9, 2021

Abstract Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved many pleiotropic functions. In human, there 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors II receptors, both transmembrane an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (activin receptor‐like 1), is mainly expressed on endothelial cells, BMPRII (BMP Receptor II), also highly directly linked rare vascular diseases: hereditary hemorrhagic telangiectasia (HHT), pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2 ) BMP10, close members the only known ligands for receptor. This specificity gives them unique role physiological pathological angiogenesis tissue homeostasis. The aim current review present overview what about BMP10 regulation particular emphasis recent results questions remain unanswered regarding roles specificities between BMP10.

Язык: Английский

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BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

Circulation Research, Год журнала: 2023, Номер 132(1), С. 109 - 126

Опубликована: Янв. 5, 2023

Pulmonary arterial hypertension forms the first and most severe of 5 categories pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling peripheral arteries, caused excessive proliferation vascular wall cells, including endothelial smooth muscle cells fibroblasts, perivascular inflammation. Compelling evidence from animal models suggests cell dysfunction a key initial trigger remodeling, which characterised hyperproliferation early apoptosis followed enrichment apoptosis-resistant populations. Dysfunctional lose their ability to produce vasodilatory mediators, together leading augmented responses, increased pressures right ventricular afterload, hypertrophy heart failure. It recognized that range abnormal cellular molecular signatures underpin pathophysiology are enhanced loss-of-function mutations in BMPR2 gene, common genetic cause associated with worse disease prognosis. Widespread metabolic abnormalities observed heart, vasculature, systemic tissues, may heterogeneity responsivity treatment. Metabolic include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine sphingosine metabolism, reduced insulin sensitivity, defective iron handling. This review critically discusses published mechanisms linking dysfunctional (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; relevance development potential therapeutic strategies.

Язык: Английский

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