LRG1 is a novel regulator of endothelial activation and is shear dependent: A Potential therapeutic target?

Pang, Ke; Fhu, Chee Wai; Ghim, Mean; Tay, Hui Min; Hou, Harry; Qu, Lu; Warboys, Christina M.; Wang, X.; Weinberg, P.D.

doi:10.1016/j.atherosclerosis.2018.06.094

Cited by 2 publications

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“…3B ). Studies have demonstrated that LRG1 promotes pathogenic neovascularization and angiogenesis through activation of TGFβ1 signaling pathway in EC 29,30 , and that it may also be involved in the inflammation-induced progression of atherosclerosis 31 . The downregulation of LRG1 strengthens the hypothesis that the applied wall shear stress has a protective effect on EC in our in vitro model.…”

Section: Resultsmentioning

confidence: 99%

Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases

Paloschi

Pauli

Winski

et al. 2022

Preprint

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Introduction: Organs-on-chips represent novel in vitro models that have the capacity to emulate aspects of human physiology and pathophysiology by incorporating features like tissue-multicellularity and exposure to organ-relevant physical environment. We developed an artery-on-a-chip with the objective to recapitulate the structure of the arterial wall composed of intimal and medial layers and the relevant hemodynamic forces that affect luminal cells. Results: By comparing arteries-on-chips exposed either to in vivo-like shear stress values or kept in static conditions, we identified a panel of novel genes modulated by shear stress. We next measured the expression pattern of shear stress-modulated genes in areas of the vascular tree affected by atherosclerotic plaques and aortic aneurysms, where disease development and progression are induced by alterations of shear stress. We obtained biopsies from patients affected by carotid artery disease (CAD), comprising the atherosclerotic plaque (diseased artery) and the adjacent region (non-diseased artery). From patients with abdominal aortic aneurysms (AAA), we obtained the aneurysmal portion (diseased aorta) and non-dilated adjacent segment (non-diseased aorta). Genes modulated by shear stress followed the same expression pattern in non-diseased segments of human vessels and were expressed by endothelial and smooth muscle cells as evidenced by immunofluorescence analysis and single cell RNA sequencing. Using mice and porcine models of vascular CAD and AAA, we confirmed that shear stress mediated targets are important in discriminating diseased and non-diseased vessel portions in vivo. Furthermore, we showed that our artery-on-a-chip can serve as a platform for drug-testing. We were able to reproduce the effects of a therapeutic agent previously used in AAA animal models in artery-on-a-chip systems and extend our understanding of its therapeutic effect through a multicellular structure. Conclusions: Our novel in vitro model is capable of mimicking important physiological aspects of human arteries, such as the response to shear stress, and can further shed light on the mechanism of action of potential therapeutics before they enter the clinical stage.

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Section: Resultsmentioning

confidence: 99%

Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases

Paloschi

Pauli

Winski

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Studies have demonstrated that LRG1 promotes pathogenic neovascularization and angiogenesis through activation of TGF𝛽1 signaling pathway in EC, [30,31] and that it may also be involved in the inflammation-induced progression of atherosclerosis. [32] Moreover, LRG1 expression in EC was found to be induced by atherogenic flow and tumor necrosis factor-𝛼 (TNF-𝛼). [33] The downregulation of LRG1 strengthens the hypothesis that the applied wall shear stress has a protective effect on EC in our in vitro model.…”

Section: Aoc-generated Targets Are Identified In Vascular Tissues And...mentioning

confidence: 99%

Utilization of an Artery‐on‐a‐Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases

Paloschi,

Pauli,

Winski

et al. 2023

Adv Healthcare Materials

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In this study, organ‐on‐chip technology is used to develop an in vitro model of medium‐to‐large size arteries, the artery‐on‐a‐chip (AoC), with the objective to recapitulate the structure of the arterial wall and the relevant hemodynamic forces affecting luminal cells. AoCs exposed either to in vivo‐like shear stress values or kept in static conditions are assessed to generate a panel of novel genes modulated by shear stress. Considering the crucial role played by shear stress alterations in carotid arteries affected by atherosclerosis (CAD) and abdominal aortic aneurysms (AAA) disease development/progression, a patient cohort of hemodynamically relevant specimens was utilized, consisting of diseased and non‐diseased (internal control) vessel regions from the same patient. Genes activated by shear stress followed the same expression pattern in non‐diseased segments of human vessels. Single cell RNA sequencing enables us to discriminate the unique cell subpopulations between non‐diseased and diseased vessel portions, revealing an enrichment of flow activated genes in structural cells originating from non‐diseased specimens. Furthermore, the AoC served as a platform for drug‐testing. It reproduced the effects of a therapeutic agent (lenvatinib) previously used in preclinical AAA studies, therefore extending our understanding of its therapeutic effect through a multicellular structure.This article is protected by copyright. All rights reserved

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LRG1 is a novel regulator of endothelial activation and is shear dependent: A Potential therapeutic target?

Cited by 2 publications

References 0 publications

Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases

Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases

Utilization of an Artery‐on‐a‐Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases

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