Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation DOI Creative Commons
Maarten M. Brandt,

Caroline Cheng,

Daphne Merkus

et al.

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

Published: Dec. 23, 2021

The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and oxygen demand across wide range of cardiac activity. Short-term regulation blood flow response to metabolic stimuli is achieved via adjustment vascular diameter different segments conjunction with mechanical forces eliciting myogenic flow-mediated vasodilation. In contrast, chronic adjustments also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes and/or density being largely modulated by acting on endothelium smooth muscle cells. Whereas recent years, substantial knowledge has been gathered regarding molecular mechanisms controlling tone how these are altered various diseases, adaptations pathologic situations less well understood. this article, we review factors involved functional alterations obstructive non-obstructive artery disease therein focus mechanobiology. Cardiovascular risk including dysregulation, hypercholesterolemia, hypertension aging have shown induce (endothelial) dysfunction Additionally, biomechanical produced stenosis associated alterations. Future studies should be directed at further unraveling underlying disease; deeper understanding critical for identification potential new targets treatment ischemic heart disease.

Language: Английский

Notch signaling pathway: architecture, disease, and therapeutics DOI Creative Commons

Binghan Zhou,

Wanling Lin,

Yaling Long

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 24, 2022

Abstract The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that signaling is an evolutionarily conserved pathway. receptors undergo three cleavages and translocate into the nucleus to regulate transcription of target genes. deeply participates in development homeostasis multiple tissues organs, aberration which results cancerous noncancerous diseases. However, recent indicate outcomes are changeable highly dependent on context. In terms cancers, can both promote inhibit tumor various types cancer. overall performance NOTCH-targeted therapies clinical trials has failed meet expectations. Additionally, mutation been proposed as a predictive biomarker for immune checkpoint blockade therapy many cancers. Collectively, pathway needs be integrally assessed with new perspectives inspire discoveries applications. this review, we focus classical latest findings related illustrate history, architecture, regulatory mechanisms, contributions physiological development, diseases, therapeutic applications microenvironment cancer immunotherapy also highlighted. We hope review will help not only beginners but experts systematically thoroughly understand

Language: Английский

Citations

649
BACE1: More than just a β‐secretase DOI Creative Commons
Hannah A. Taylor,

Lena Przemyłska,

Eva M. Clavane

et al.

Obesity Reviews, Journal Year: 2022, Volume and Issue: 23(7)

Published: Feb. 4, 2022

Summary β‐site amyloid precursor protein cleaving enzyme‐1 (BACE1) research has historically focused on its actions as the β‐secretase responsible for production of β‐amyloid beta, observed in Alzheimer's disease. Although greatest expression BACE1 is found brain, mRNA and also many cell types including pancreatic β‐cells, adipocytes, hepatocytes, vascular cells. Pathologically elevated these cells been implicated development metabolic diseases, type 2 diabetes, obesity, cardiovascular In this review, we examine key questions surrounding literature, how regulated dysregulation may occur disease, understand regulates metabolism via cleavage a myriad substrates. The phenotype knockout mice models, reduced weight gain, increased energy expenditure, enhanced leptin signaling, proposes physiological role regulating homeostasis. Taken together with loss inhibitors clinical trials, data highlight novel regulation physiology. Finally, review aims to possibility that could provide innovative treatment obesity comorbidities.

Language: Английский

Citations

65
Hippo signaling pathway and respiratory diseases DOI Creative Commons
Weifeng Tang, Min Li,

Xiaoting Yangzhong

et al.

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: April 20, 2022

The hippo signaling pathway is a highly conserved evolutionary that plays an important role in regulating cell proliferation, organ size, tissue development, and regeneration. Increasing evidences consider the involved process of respiratory diseases. Hippo mainly composed mammalian STE20-like kinase 1/2 (MST1/2), large tumor suppressor (LATS1/2), WW domain Sav family containing protein 1 (SAV1), MOB activator (MOB1), Yes-associated (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ), members TEA (TEAD) family. YAP cascade effector pathway. activation promotes pulmonary arterial vascular smooth muscle cells (PAVSMCs) which leads to remodeling; thereby hypertension (PAH) aggravated. While loss high expression inflammatory genes accumulation cells, pneumonia consequently exacerbated. In addition, overexpressed proliferation lung fibroblasts collagen deposition; idiopathic fibrosis (IPF) promoted. Moreover, knockout reduces deposition senescence adult alveolar epithelial (AECs); hence IPF slowed. may be repair acute injury (ALI) by promoting differentiation progenitor intervening capillary endothelium. asthma. conclusion, More researches are needed focus on molecular mechanisms participates

Language: Английский

Citations

44
Notch signalling in healthy and diseased vasculature DOI Creative Commons
Francesca Del Gaudio, Dongli Liu, Urban Lendahl

et al.

Open Biology, Journal Year: 2022, Volume and Issue: 12(4)

Published: April 1, 2022

Notch signalling is an evolutionarily highly conserved mechanism governing differentiation and regulating homeostasis in many tissues. In this review, we discuss recent advances our understanding of the roles that plays vasculature. We describe how regulates different steps during genesis remodelling blood vessels (vasculogenesis angiogenesis), including critical assigning arterial venous identities to emerging regulation their branching. then proceed experimental perturbation vasculature later development affects vascular homeostasis. also dysregulated signalling, as a consequence direct mutations genes pathway or aberrant output, contributes various types disease, CADASIL, Snedden syndrome pulmonary hypertension. Finally, point out some current knowledge gaps identify remaining challenges role vasculature, which need be addressed pave way for Notch-based therapies cure ameliorate disease.

Language: Английский

Citations

43
Therapeutic RNA Strategies for Chronic Obstructive Pulmonary Disease DOI
Dan Mei, W.S. Daniel Tan, Yvonne Tay

et al.

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(7), P. 475 - 486

Published: May 17, 2020

Language: Английский

Citations

53
mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target DOI Open Access
Aleksandra Babicheva, Ayako Makino,

Jason X.‐J. Yuan

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 2144 - 2144

Published: Feb. 21, 2021

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without cure. The exact pathogenic mechanisms of PAH are complex poorly understood, yet number abnormally expressed genes regulatory pathways contribute to sustained vasoconstriction vascular remodeling the distal pulmonary arteries. Mammalian target rapamycin (mTOR) one major signaling implicated in regulating cell proliferation, migration, differentiation, protein synthesis. Here we will describe canonical mTOR pathway, structural functional differences between complexes 1 2, as well crosstalk with other important cascades development PAH. role due its contribution phenotypic transition, gene regulation artery smooth muscle endothelial cells be discussed. Despite progress our elucidation etiology pathogenesis over two last decades, there lack effective therapeutic agents treat patients representing significant unmet clinical need. In this review, explore possibility potential use inhibitors cascade

Language: Английский

Citations

43
JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension DOI
Yu Zhang, Moises Hernandez,

Jonathan R. Gower

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(643)

Published: May 4, 2022

Within the pulmonary arterial tree, NOTCH3 pathway is crucial in controlling vascular smooth muscle cell proliferation and maintaining cells an undifferentiated state. Pulmonary hypertension (PAH) a fatal disease without cure, characterized by elevated resistance due to precapillary arteries, perivascular inflammation, asymmetric neointimal hyperplasia. Here, we show that human PAH overexpression of NOTCH ligand JAGGED-1 (JAG-1) small artery JAG-1 selectively controls signaling cellular autocrine fashion. In contrast, DELTA-LIKE 4 minimally expressed from individuals with PAH, inhibits cleavage signaling, retards proliferation. A new monoclonal antibody for treatment which blocks cis- trans-induced receptor vasculature, was developed. Inhibition JAG-1-induced lung reverses clinical pathologic two rodent models disease, toxic side effects associated nonspecific inhibitors. Our data suggest opposing roles ligands vasculature hypertension. We propose targeting activation may be effective, safe strategy treat PAH.

Language: Английский

Citations

32
Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca2+ signaling DOI

Angela Balistrieri,

Ayako Makino, Jason X.‐J. Yuan

et al.

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(3), P. 1827 - 1897

Published: Nov. 24, 2022

The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive entire cardiac output. Pulmonary arterial pressure function of output vascular resistance, resistance inversely proportional fourth power intraluminal radius artery. Therefore, very small decrease lumen diameter results in significant increase pressure. hypertension fatal progressive disease with poor prognosis. Regardless initial pathogenic triggers, sustained vasoconstriction, concentric remodeling, occlusive intimal lesions, situ thrombosis, wall stiffening are major direct causes for elevated patients other forms precapillary hypertension. In this review, we aim discuss basic principles physiological mechanisms involved regulation lung hemodynamics function, changes vasculature contribute increased pressure, development progression We focus on reviewing roles membrane receptors, ion channels, intracellular Ca

Language: Английский

Citations

30
Pulmonary Hypertension in 2021: Part I—Definition, Classification, Pathophysiology, and Presentation DOI
Theresa A. Gelzinis

Journal of Cardiothoracic and Vascular Anesthesia, Journal Year: 2021, Volume and Issue: 36(6), P. 1552 - 1564

Published: July 8, 2021

Language: Английский

Citations

39
Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung-Function Decline DOI
Laura Vera, Paula García‐Olloqui,

Eva Petri

et al.

American Journal of Respiratory Cell and Molecular Biology, Journal Year: 2021, Volume and Issue: 64(4), P. 465 - 476

Published: Jan. 25, 2021

Fibroblast activation includes differentiation to myofibroblasts and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast several tissues, including the lung. Here, we identify subset collagen-expressing cells lung that exhibit Notch3 activity at homeostasis. After injury, this increases, being found αSMA-expressing mouse human fibrotic Although previous studies suggest contribution stromal activation, vivo evidence role fibrosis remains unknown. In study, examine effects deletion pulmonary demonstrate Notch3-deficient lungs are protected from injury with significantly reduced collagen deposition after bleomycin administration. induction profibrotic genes bleomycin-treated Notch3-knockout consistently present fewer αSMA-positive myofibroblasts. As result, volume healthy tissue higher function improved absence Notch3. Using vitro cultures primary fibroblasts, confirmed participates their survival differentiation. Thus, deficiency mitigates development because its mediating fibroblast activation. Our findings reveal previously unidentified mechanism underlying fibrogenesis provide potential novel therapeutic approach target

Language: Английский

Citations

35