TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities

The Journal of Pathology, Journal Year: 2021, Volume and Issue: 254(4), P. 358 - 373

Published: April 9, 2021

Many chronic diseases are marked by fibrosis, which is defined an abundance of activated fibroblasts and excessive deposition extracellular matrix, resulting in loss normal function the affected organs. The initiation progression fibrosis elaborated pro-fibrotic cytokines, most critical transforming growth factor-β1 (TGF-β1). This review focuses on fibrogenic roles increased TGF-β activities underlying signaling mechanisms fibroblast population other cell types that contribute to fibrosis. Insight into these as a universal driver has stimulated development therapeutic interventions attenuate progression, based interference with signaling. Their promise preclinical clinical settings will be discussed. © 2021 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.

Language: Английский

---

Endothelial-Mesenchymal Transition in Cardiovascular Disease

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2021, Volume and Issue: 41(9), P. 2357 - 2369

Published: July 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.

Language: Английский

---

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 15, 2021

Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial can promote chronic inflammation disease processes like thrombosis, atherosclerosis, lung injury. In cells, mitochondria regulate these pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that initiate exacerbate senescence, a state promotes dysfunction. Oxidative also activate feedback loops perpetuate dysfunction, overproduction, inflammation. this review, we provide an overview of phenotypes mediated by - such inflammation, senescence well how states may be initiated cells. We propose activates mtROS-mediated cause long-term changes host status function, promoting cardiovascular injury after recovery from COVID-19. Finally, discuss the implications proposed on vascular health potential treatments to address conditions.

Language: Английский

---

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Dec. 22, 2021

Atherosclerosis, the chronic accumulation of cholesterol-rich plaque within arteries, is associated with a broad spectrum cardiovascular diseases including myocardial infarction, aortic aneurysm, peripheral vascular disease, and stroke. Atherosclerotic disease remains leading cause mortality in high-income countries recent years have witnessed notable increase prevalence low- middle-income regions world. Considering this prominent evolving global burden, there need to identify cellular mechanisms that underlie pathogenesis atherosclerosis discover novel therapeutic targets for preventing or mitigating its clinical sequelae. Despite decades research, we still do not fully understand complex cell-cell interactions drive atherosclerosis, but new investigative approaches are rapidly shedding light on these essential mechanisms. The endothelium resides at interface systemic circulation underlying vessel wall plays an role governing pathophysiological processes during atherogenesis. In review, present emerging evidence implicates activated as driver by directing site-specificity formation promoting development through intracellular processes, which regulate endothelial cell proliferation turnover, metabolism, permeability, plasticity. Moreover, highlight intercellular communication cells modulate activity key populations involved atherogenesis, discuss how contribute resolution biology - process dysregulated advanced plaques. Finally, describe important future directions preclinical epigenetic targeted therapies, limit progression at-risk affected patients.

Language: Английский

---

Transforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities

Chemico-Biological Interactions, Journal Year: 2022, Volume and Issue: 369, P. 110289 - 110289

Published: Nov. 29, 2022

Language: Английский

---

Endothelial mechanobiology in atherosclerosis

Cardiovascular Research, Journal Year: 2023, Volume and Issue: 119(8), P. 1656 - 1675

Published: May 10, 2023

Abstract Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays central role in maintaining integrity and homeostasis direct contact with flow. Research over past century has shown that mechanical perturbations wall contribute to formation progression atherosclerosis. While straight part artery exposed sustained laminar flow physiological high shear stress, near branch points or curved vessels can exhibit ‘disturbed’ Clinical studies as well carefully controlled vitro analyses have confirmed these regions disturbed flow, include low recirculation, oscillation, lateral are preferential sites atherosclerotic lesion formation. Because their critical homeostasis, endothelial cells (ECs) mechanosensory mechanisms allow them react rapidly changes forces, execute context-specific adaptive responses modulate EC functions. This review summarizes current understanding mechanobiology, guide identification new therapeutic targets slow reverse

Language: Английский

---

Injectable hydrogels for cartilage and bone tissue regeneration: A review

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 246, P. 125674 - 125674

Published: July 4, 2023

Language: Английский

---

Vascular Inflammatory Diseases and Endothelial Phenotypes

Cells, Journal Year: 2023, Volume and Issue: 12(12), P. 1640 - 1640

Published: June 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.

Language: Английский

---

TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

Aging and Disease, Journal Year: 2023, Volume and Issue: 14(5), P. 1633 - 1633

Published: Jan. 1, 2023

Fibrosis is the abnormal accumulation of extracellular matrix proteins such as collagen and fibronectin. Aging, injury, infections, inflammation can cause different types tissue fibrosis. Numerous clinical investigations have shown a correlation between degree liver pulmonary fibrosis in patients telomere length mitochondrial DNA content, both which are signs aging. Aging involves gradual loss function over time, results homeostasis and, ultimately, an organism's fitness. A major feature aging senescent cells. Senescent cells abnormally continuously accumulate late stages life, contributing to age-related deterioration, among other characteristics. Furthermore, generates chronic inflammation, decreases organ function. This finding suggests that closely related. The transforming growth factor-beta (TGF-β) superfamily plays crucial role physiological pathological processes aging, immune regulation, atherosclerosis, In this review, functions TGF-β normal organs, fibrotic tissues discussed: signalling altered with age indicator pathology associated addition, review discusses potential targeting noncoding.

Language: Английский

---

Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(736)

Published: Feb. 28, 2024

Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it unclear to what extent endothelial cells also might contribute. We detected increased expression the transcription factor Sox9 in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic high-fat diet and nitric oxide synthase inhibition, pulmonary bleomycin treatment, liver due choline-deficient diet. observed up-regulation SOX9 cardiac tissue from patients with failure. To test whether induction was sufficient cause disease, we generated mice cell–specific overexpression , which promoted multiple organs resulted signs Endothelial deletion prevented organ dysfunction two as well lung Bulk single-cell RNA sequencing across vascular beds revealed that extracellular matrix, growth factor, inflammatory gene expression, leading matrix deposition cells. Moreover, activated neighboring then migrated deposited response SOX9, process partly mediated secreted CCN2, direct target; reversed these changes. findings suggest role for fibrosis-promoting during disease imply an important regulator fibrosis.

Language: Английский

---