Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2

Hsu, Bernadette Y.; Bae, Yongho; Mui, Keeley L.; Liu, Shulin; Assoian, Richard K.

doi:10.1371/journal.pone.0128974

Cited by 14 publications

(15 citation statements)

References 29 publications

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“…Inhibition of YAP/TAZ signaling yields fourfold increases in COX-2 expression, increasing COX-2 and prostaglandin levels well above those seen even on relatively soft matrix. Of note, the changes in cytoskeletal organization following YAP/TAZ inhibition resemble alterations secondary to Rho and Rho kinase inhibition, which have been shown to lead to similar increases in COX-2 levels in VSMC (27). We further demonstrate that overexpression of either YAP or TAZ dramatically reduces COX-2 and secreted prostaglandins to near undetectable levels.…”

Section: Discussionsupporting

confidence: 65%

Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

Dieffenbach

Haeger

Coronata

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary arterial stiffness is an independent risk factor for mortality in pulmonary hypertension (PH) and plays a critical role in PH pathophysiology. Our laboratory has recently demonstrated arterial stiffening early in experimental PH, along with evidence for a mechanobiological feedback loop by which arterial stiffening promotes further cellular remodeling behaviors (Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suárez Velandia MM, Vitali S, Colas RA, Norris PC, Marinković A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Fredenburgh LE. 1: e86987, 2016). Cyclooxygenase-2 (COX-2) and prostaglandin signaling have been implicated in stiffness-mediated regulation, with prostaglandin activity inversely correlated to matrix stiffness and remodeling behaviors in vitro, as well as to disease progression in rodent PH models. The mechanism by which mechanical signaling translates to reduced COX-2 activity in pulmonary vascular cells is unknown. The present work investigated the transcriptional regulators Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1, a.k.a., TAZ), which are known drivers of downstream mechanical signaling, in mediating stiffness-induced changes in COX-2 and prostaglandin activity in pulmonary artery smooth muscle cells (PASMCs). We found that YAP/TAZ activity is increased in PAH PASMCs and experimental PH and is necessary for the development of stiffness-dependent remodeling phenotypes. Knockdown of YAP and TAZ markedly induces COX-2 expression and downstream prostaglandin production by approximately threefold, whereas overexpression of YAP or TAZ reduces COX-2 expression and prostaglandin production to near undetectable levels. Together, our findings demonstrate a stiffness-dependent YAP/TAZ-mediated positive feedback loop that drives remodeling phenotypes in PASMCs via reduced COX-2 and prostaglandin activity. The ability to interrupt this critical mechanobiological feedback loop and enhance local prostaglandin activity via manipulation of YAP/TAZ signaling presents a highly attractive novel strategy for the treatment of PH.

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Section: Discussionsupporting

confidence: 65%

Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

Dieffenbach

Haeger

Coronata

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It is well known that ECs respond to the mechanical properties of their matrix (Hsu et al , 2015; Kohn and Lampi et al , 2015; Kohn and Zhou et al ., 2015 Stroka and Aranda-Espinoza, 2011a). Matrix stiffness can regulate EC traction forces, contractility, and F-actin stress fiber formation through Rho/ROCK/MLCK signaling (Birukova et al , 2013; Hsu et al , 2015; Huynh et al, 2011; Ridley, 2001; Stroka and Aranda-Espinoza, 2011a; Szulcek et al , 2013). AFM elastic modulus maps described here indicate that aged-sedentary mice have more heterogeneous elastic modulus profiles.…”

Section: Discussionmentioning

confidence: 99%

Mechanical heterogeneities in the subendothelial matrix develop with age and decrease with exercise

Kohn

Chen

Cheng

et al. 2016

Journal of Biomechanics

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Arterial stiffening occurs with age and is associated with lack of exercise. Notably both age and lack of exercise are major cardiovascular risk factors. While it is well established that bulk arterial stiffness increases with age, more recent data suggest that the intima, the innermost arterial layer, also stiffens during aging. Micro-scale mechanical characterization of individual layers is important because cells primarily sense the matrix that they are in contact with and not necessarily the bulk stiffness of the vessel wall. To investigate the relationship between age, exercise, and subendothelial matrix stiffening, atomic force microscopy was utilized here to indent the subendothelial matrix of the thoracic aorta from young, aged-sedentary, and aged-exercised mice, and elastic modulus values were compared to conventional pulse wave velocity measurements. The subendothelial matrix elastic modulus was elevated in aged-sedentary mice compared to young or aged-exercised mice, and the macro-scale stiffness of the artery was found to linearly correlate with the subendothelial matrix elastic modulus. Notably, we also found that with age, there exists an increase in the point-to-point variations in modulus across the subendothelial matrix, indicating non-uniform stiffening. Importantly, this heterogeneity is reversible with exercise. Given that vessel stiffening is known to cause aberrant endothelial cell behavior, and the spatial heterogeneities we find exist on a length scale much smaller than the size of a cell, these data suggest that further investigation in the heterogeneity of the subendothelial matrix elastic modulus is necessary to fully understand the effects of physiological matrix stiffening on cell function.

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“…Primary human vascular smooth muscle cells (ATCC) and mouse VSMCs (Cell Biologics) were cultured as previously described [8,11,63]. Human and mouse VSMCs were used at passages 3-8 and 3-5, respectively.…”

Section: Cell Culture and Drug Treatmentmentioning

confidence: 99%

Machine learning reveals heterogeneous responses to FAK, Rac, Rho, and Cdc42 inhibition on vascular smooth muscle cell spheroid formation and morphology

Vaidyanathan

Wang

Krajnik

et al. 2020

Preprint

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Hyper proliferation of vascular smooth muscle cells (VSMCs) contributes to neointima formation in atherosclerosis and the response to vascular injury. Understanding how to control VSMC proliferation would advance the effort to treat vascular disease. Drug responses are often different among patients with the same vascular disease condition, making it difficult to cater patientspecific treatments (existence of heterogeneity). Thus, we examined variations in response to drug treatments using VSMC spheroids that mimic vascular disease condition in vivo. FAK and its downstream Rho GTPases (Rac, Rho, and Cdc42) control cell-cell contact and play a key role in vascular pathology. Here, we tested the importance of FAK and Rho GTPases in spheroid formation. VSMC spheroids were made using a hanging-drop method with either inhibitors or vehicle control. Changes in morphology were used as a key indicator of spheroid response to drug treatment. A machine learning (ML) image segmentation (VGG16-U-net) was used to segment the spheroid images. After the morphological features were extracted from the segmented images, a two-level cluster framework was used to cluster VSMC spheroids into different morphologies. We found that FAK and Rho GTPases are required for normal spheroid formation. Next, we analyzed the various morphologies of disrupted spheroids resulting from drug treatment using our ML pipeline. The first-level clustering analysis showed the presence of 4 clusters of spheroids with rounded and disrupted morphologies. The subsequent second-level clustering analysis identified the presence of four distinct morphological clusters among these disrupted spheroids, and they exhibited differential responses to FAK and Rho GTPases inhibition. Particularly, we found FAK and Rho specific morphological phenotypes, thus suggesting that there may be two distinct pathways governing VSMC spheroid formation.Collectively, we revealed there are significant heterogeneities in the drug responses of spheroid formation, which were overlooked in previous analyses. This is our first step towards developing the ML-based method that can be used to assess the effects of different drugs on the VSMC spheroid model for better characterization of pathologic progression of vascular disease.

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Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2

Cited by 14 publications

References 29 publications

Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

Mechanical heterogeneities in the subendothelial matrix develop with age and decrease with exercise

Machine learning reveals heterogeneous responses to FAK, Rac, Rho, and Cdc42 inhibition on vascular smooth muscle cell spheroid formation and morphology

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