Haemodynamics Regulate Fibronectin Assembly via PECAM

Chen, Zhongming; Givens, Chris; Reader, John S.; Tzima, Ellie

doi:10.1038/srep41223

Cited by 8 publications

(5 citation statements)

References 50 publications

(71 reference statements)

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“…Fibronectin, a protein previously known to be enriched in CADASIL vessels and shown to increase levels in blood vessels of CADASIL patients ( 18 ), was upregulated and demonstrated clinical congruence with disease progression in the CADASIL-Early cohort. While FN1 plays a critical role in vascular remodeling after hypoxia- or hypertension-induced vessel injury ( 65, 66 ), its aggregation in tissues may be detrimental by promotion of thrombogenesis ( 67, 68 ), neuroinflammation ( 69 ), and arrest of myelination ( 70 ), all thought to be components of chronic cSVD and stroke-related VCID. Upregulated CADASIL FN1 levels were positively associated with increased cerebral atrophy and cognitive deterioration in our Early cohort, emerging as a critical, possibly neurodegenerative factor in CADASIL, which warrants exploration in future studies.…”

Section: Discussionmentioning

confidence: 99%

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

Keller,

Radabaugh,

Karvelas

et al. 2024

Preprint

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of vascular cognitive impairment and dementia. A genetic arteriolosclerotic disease, the molecular mechanisms driving vascular brain degeneration and decline remain unclear. With the goal of driving discovery of disease-relevant biological perturbations in CADASIL, we used machine learning approaches to extract proteomic disease signatures from large-scale proteomics generated from plasma collected from three distinct cohorts in US and Colombia: CADASIL-Early (N = 53), CADASIL-Late (N = 45), and CADASIL-Colombia (N = 71). We extracted molecular signatures with high predictive value for early and late-stage CADASIL and performed robust cross- and external-validation. We examined the biological and clinical relevance of our findings through pathway enrichment analysis and testing of associations with clinical outcomes. Our study represents a model for unbiased discovery of molecular signatures and disease biomarkers, combining non-invasive plasma proteomics with clinical data. We report on novel disease-associated molecular signatures for CADASIL, derived from the accessible plasma proteome, with relevance to vascular cognitive impairment and dementia.

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Section: Discussionmentioning

confidence: 99%

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

Keller,

Radabaugh,

Karvelas

et al. 2024

Preprint

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“…In this report, we have described an affordable and reproducible experimental method to study the effect of cancer therapy on atherosclerotic lesion formation. In addition, atherosclerosis lesion formation at the aortic root and aortic arch areas may not be directly related to disturbed flow-induced atherogenesis, because it has been reported that fibronection expression is higher in these areas ( 35 ). By focusing on the lesions formed after PCL, we can evaluate the role of disturbed flow in cancer therapy-mediated vascular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors

Wang

Kotla

et al. 2018

Front. Cardiovasc. Med.

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BackgroundThe high incidence of cardiovascular events in cancer survivors has long been noted, but the mechanistic insights of cardiovascular toxicity of cancer treatments, especially for vessel diseases, remain unclear. It is well known that atherosclerotic plaque formation begins in the area exposed to disturbed blood flow, but the relationship between cancer therapy and disturbed flow in regulating plaque formation has not been well studied. Therefore, we had two goals for this study; (1) Generate an affordable, reliable, and reproducible mouse model to recapitulate the cancer therapy-induced cardiovascular events in cancer survivors, and (2) Establish a mouse model to investigate the interplay between disturbed flow and various cancer therapies in the process of atherosclerotic plaque formation.Methods and ResultsWe examined the effects of two cancer drugs and ionizing radiation (IR) on disturbed blood flow-induced plaque formation using a mouse carotid artery partial ligation (PCL) model of atherosclerosis. We found that doxorubicin and cisplatin, which are commonly used anti-cancer drugs, had no effect on plaque formation in partially ligated carotid arteries. Similarly, PCL-induced plaque formation was not affected in mice that received IR (2 Gy) and PCL surgery performed one week later. In contrast, when PCL surgery was performed 26 days after IR treatment, not only the atherosclerotic plaque formation but also the necrotic core formation was significantly enhanced. Lastly, we found a significant increase in p90RSK phosphorylation in the plaques from the IR-treated group compared to those from the non-IR treated group.ConclusionsOur results demonstrate that IR not only increases atherosclerotic events but also vulnerable plaque formation. These increases were a somewhat delayed effect of IR as they were observed in mice with PCL surgery performed 26 days, but not 10 days, after IR exposure. A proper animal model must be developed to study how to minimize the cardiovascular toxicity due to cancer treatment.

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“…3). The Fiji image analysis software (Chen et al, 2017) and morphological analysis (Canver & Morss Clyne, 2017) were also used to analyze FN orientation. The Fiji image analysis software quantified FN alignment by implementing Fourier analysis which has limited ability to distinguish small fiber alignment changes (Palmer & Bizios, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Fourier analysis (Ng et al, 2005; Marquez, 2006), edge detection (Yoshigi et al, 2003; Vartanian et al, 2008), and fractal analysis (Fuseler et al, 2007) are commonly used to quantitatively analyze actin fiber alignment. Recently, several new studies have quantified FN alignment with edge detection (Figueroa et al, 2014), morphological analysis and (Canver & Morss Clyne, 2017) the Fiji image analysis software (Chen et al, 2017). Nevertheless, edge detection and Fiji image analysis software may not suitable for FN quantification because FN fibers displayed in fluorescence images have poorly defined borders and multiple branch points (Figueroa et al, 2014; Chen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several new studies have quantified FN alignment with edge detection (Figueroa et al, 2014), morphological analysis and (Canver & Morss Clyne, 2017) the Fiji image analysis software (Chen et al, 2017). Nevertheless, edge detection and Fiji image analysis software may not suitable for FN quantification because FN fibers displayed in fluorescence images have poorly defined borders and multiple branch points (Figueroa et al, 2014; Chen et al, 2017). Skeletonization of the FN fiber into a 1-pixel thickness structure during the process of morphological analysis may result in loss of information of FN orientation (Canver & Morss Clyne, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Studies of Endothelial Cell Fibronectin and Filamentous Actin (F-Actin) Coalignment in Response to Shear Stress

Gong

Zhao

et al. 2017

Microsc Microanal

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Both fibronectin (FN) and filamentous actin (F-actin) fibers play a critical role for endothelial cells (ECs) in responding to shear stress and modulating cell alignment and functions. FN is dynamically coupled to the F-actin cytoskeleton via focal adhesions. However, it is unclear how ECs cooperatively remodel their subcellular FN matrix and intracellular F-actin cytoskeleton in response to shear stress. Current studies are hampered by the lack of a reliable and sensitive quantification method of FN orientation. In this study, we developed a MATLAB-based feature enhancement method to quantify FN and F-actin orientation. The role of F-actin in FN remodeling was also studied by treating ECs with cytochalasin D. We have demonstrated that FN and F-actin codistributed and coaligned parallel to the flow direction, and that F-actin alignment played an essential role in regulating FN alignment in response to shear stress. Our findings offer insight into how ECs cooperatively remodel their subcellular ECM and intracellular F-actin cytoskeleton in response to mechanical stimuli, and are valuable for vascular tissue engineering.

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Haemodynamics Regulate Fibronectin Assembly via PECAM

Cited by 8 publications

References 50 publications

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors

Quantitative Studies of Endothelial Cell Fibronectin and Filamentous Actin (F-Actin) Coalignment in Response to Shear Stress

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