Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

Ferreira, Fernanda Silva; Souza, Lucas Eduardo Botelho de; Thomé, Carolina Hassibe; Pinto, Mariana Tomazini; Origassa, Clarice Silvia Taemi; Salustiano, Suellen Gomes; Faça, Vítor Marcel; Câmara, Niels Olsen Saraiva; Kashima, Simone; Covas, Dimas Tadeu

doi:10.3390/ijms20030458

Cited by 29 publications

(26 citation statements)

References 33 publications

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“…IPF is a progressive, chronic, and ultimately fatal interstitial lung disease characterized by enhanced extracellular matrix deposition. Although the exact etiology in IPF is unclear, complex, and probably diverse, previous studies have identified EndoMT as one of the important processes for the establishment and progression of the fibrotic changes . In our study, we also found that all control groups showed no abnormalities, while WT‐BLM mice showed significant fibrotic responses in the lung; these were accompanied by decreased endothelial markers VE‐cadherin and CD31 but increased mesenchymal cell marker α‐smooth muscle actin (α‐SMA), indicating EndoMT.…”

Section: Discussionsupporting

confidence: 70%

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Tang

Mao

et al. 2019

FASEB j.

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Src Homology 2‐containing Inositol Phosphatase‐1 (SHIP‐1) is a target of miR‐155, a pro‐inflammatory factor. Deletion of the SHIP‐1 gene in mice caused spontaneous lung inflammation and fibrosis. However, the role and function of endothelial miR‐155 and SHIP‐1 in lung fibrosis remain unknown. Using whole‐body miR‐155 knockout mice and endothelial cell–specific conditional miR‐155 (VEC‐Cre‐miR‐155 or VEC‐miR‐155) or SHIP‐1 (VEC‐SHIP‐1) knockout mice, we assessed endothelial‐mesenchymal transition (EndoMT) and fibrotic responses in bleomycin (BLM) induced lung fibrosis models. Primary mouse lung endothelial cells (MLEC) and human umbilical vein endothelial cells (HUVEC) with SHIP‐1 knockdown were analyzed in TGF‐β1 or BLM, respectively, induced fibrotic responses. Fibrosis and EndoMT were significantly reduced in miR‐155KO mice and changes in EndoMT markers in MLEC after TGF‐β1 stimulation confirmed the in vivo findings. Furthermore, lung fibrosis and EndoMT responses were reduced in VEC‐miR‐155 mice but significantly enhanced in VEC‐SHIP‐1 mice after BLM challenge. SHIP‐1 knockdown in HUVEC cells resulted in enhanced EndoMT induced by BLM. Meanwhile, these changes involved the PI3K/AKT, JAK/STAT3, and SMAD/STAT signaling pathways. These studies demonstrate that endothelial miR‐155 plays an important role in fibrotic responses in the lung through EndoMT. Endothelial SHIP‐1 is essential in controlling fibrotic responses and SHIP‐1 is a target of miR‐155. Endothelial cells are an integral part in lung fibrosis.

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Section: Discussionsupporting

confidence: 70%

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Tang

Mao

et al. 2019

FASEB j.

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“…Unlike HUVEC, HMEC-1 do not respond mechanically to addition of TGF-β2, a discrepancy which is consistent with TGF-β2 not being a stiffness-sensitive DEG for HMEC-1. Different EC types are well known to exhibit local morphological and functional specializations and distinct gene expression profiles depending on the tissue they originate from 75 and can therefore respond differently to cytokines including TGF-β2 76 . Which EC types are sensitive to TGF-β2 and how much that depends on the anatomical location they come from or their local microenvironment, including its mechanics, could be the focus of future studies.…”

Section: Discussionmentioning

confidence: 99%

Subendothelial stiffness alters endothelial cell traction force generation while exerting a minimal effect on the transcriptome

Bastounis

Yeh

Theriot

2019

Sci Rep

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Endothelial cells respond to changes in subendothelial stiffness by altering their migration and mechanics, but whether those responses are due to transcriptional reprogramming remains largely unknown. We measured traction force generation and also performed gene expression profiling for two endothelial cell types grown in monolayers on soft or stiff matrices: primary human umbilical vein endothelial cells (HUVEC) and immortalized human microvascular endothelial cells (HMEC-1). Both cell types respond to changes in subendothelial stiffness by increasing the traction stresses they exert on stiffer as compared to softer matrices, and exhibit a range of altered protein phosphorylation or protein conformational changes previously implicated in mechanotransduction. However, the transcriptome has only a minimal role in this conserved biomechanical response. Only few genes were differentially expressed in each cell type in a stiffness-dependent manner, and none were shared between them. In contrast, thousands of genes were differentially regulated in HUVEC as compared to HMEC-1. HUVEC (but not HMEC-1) upregulate expression of TGF-β2 on stiffer matrices, and also respond to application of exogenous TGF-β2 by enhancing their endogenous TGF-β2 expression and their cell-matrix traction stresses. Altogether, these findings provide insights into the relationship between subendothelial stiffness, endothelial mechanics and variation of the endothelial cell transcriptome, and reveal that subendothelial stiffness, while critically altering endothelial cells’ mechanical behavior, minimally affects their transcriptome.

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“…TGFβ treatment of PAECs induces the expression of the EndoMT transcription factors TWIST1 and SNAIL1 [ 103 , 108 ] and the mesenchymal markers α-SMA and phospho-vimentin [ 109 ] ( Figure 4 ). TWIST1 increases the expression of TGFβ, leading to enhanced TGFβ signaling [ 110 ].…”

Section: Features Of Ec Dysfunctionmentioning

confidence: 99%

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

et al. 2021

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Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.

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Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

Cited by 29 publications

References 33 publications

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Subendothelial stiffness alters endothelial cell traction force generation while exerting a minimal effect on the transcriptome

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

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