Endothelial Fate Mapping in Mice With Pulmonary Hypertension

Qiao, Liang; Nishimura, Toshihiko; Shi, Lingfang; Sessions, Dane; Thrasher, Ama; Trudell, James R.; Berry, Gerald J.; Pearl, Ronald G.; Kao, Peter N.

doi:10.1161/circulationaha.113.003734

Cited by 80 publications

(84 citation statements)

References 41 publications

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“…16,52 To gain insights into the mechanisms regulating this process, we found that the expression of primary cilia in the aorta of Westerntype diet fed LDLR −/− mice was restricted to nonaffected areas, characterized by PECAM-1-expressing ECs. On the contrary, primary cilia or PECAM-1 were not observed in ECs at SLUGpositive regions, suggesting a loss of the endothelial phenotype.…”

Section: Discussionmentioning

confidence: 99%

SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification

Sánchez‐Duffhues

Vinuesa

Lindeman

et al. 2015

ATVB

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Objective-Arterial calcification is considered a major cause of death and disabilities worldwide because the associated vascular remodeling leads to myocardial infarction, stroke, aneurysm, and pulmonary embolism. This process occurs via poorly understood mechanisms involving a variety of cell types, intracellular mediators, and extracellular cues within the vascular wall. An inverse correlation between endothelial primary cilia and vascular calcified areas has been described although the signaling mechanisms involved remain unknown. We aim to investigate the signaling pathways regulated by the primary cilium that modulate the contribution of endothelial cells to vascular calcification. Approach and Results-We found that human and murine endothelial cells lacking primary cilia are prone to undergo mineralization in response to bone morphogenetic proteins stimulation in vitro. Using the Tg737 orpk/orpk cillium-defective mouse model, we show that nonciliated aortic endothelial cells acquire the ability to transdifferentiate into mineralizing osteogenic cells, in a bone morphogenetic protein-dependent manner. We identify β-CATENIN-induced SLUG as a key transcription factor controlling this process. Moreover, we show that the endothelial expression of SLUG is restricted to atheroprone areas in the aorta of LDLR −/− mice. Finally, we demonstrate that SLUG and phospho-homolog of the Drosophila protein, mothers against decapentaplegic (MAD) and the Caenorhabditis elegans protein SMA (from gene sma for small body size)-1/5/8 expression increases in endothelial cells constituting the vasa vasorum in the human aorta during the progression toward atherosclerosis. Conclusions-We demonstrated that the lack of primary cilia sensitizes the endothelium to undergo bone morphogenetic protein-dependent-osteogenic differentiation. These data emphasize the role of the endothelial cells on the vascular calcification and uncovers SLUG as a key target in atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification

Sánchez‐Duffhues

Vinuesa

Lindeman

et al. 2015

ATVB

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“…Although additional experiments are required to identify the involved factors, these findings clearly support the idea that pulmonary pericytes are a potential in situ source of SM-like cells that could contribute to PAH pulmonary vascular remodeling. Interestingly, Qiao et al 56 also recently demonstrated that the endothelial-to-mesenchymal transition is another mechanism contributing to SM hyperplasia in PAH. Activation of proteases intervenes in proteolytic processing of the extracellular matrix, with release of growth factors (FGF-2, TGF-β, vascular endothelial growth factor, and PDGF) stored in their heparin-like glycosaminoglycans, actively contributing to changes of the cellular microenvironment, which can also result in modification of the pericyte differentiation state.…”

Section: Ricard Et Al Pericytes In Pulmonary Arterial Hypertension 1593mentioning

confidence: 99%

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

et al. 2014

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P ulmonary arterial hypertension (PAH) is a rapidly progressive disease characterized by obstructive remodeling of distal pulmonary arteries (<500 μm), leading to a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. There is currently no cure for PAH, which has a very poor prognosis (mean survival of 2.8 years).1 It is well known that pulmonary arteries display complex structural and functional changes in PAH and that pulmonary endothelial cell (EC) dysfunction plays a crucial role in the disease progression. Despite an increased knowledge in the past years about PAH pathobiological cellular and molecular mechanisms, we still do not know what initiates this disease and its characteristic pulmonary vascular remodeling. Editorial see p 1545 Clinical Perspective on p 1597Pericytes are central regulators of vascular development, stabilization, maturation, and remodeling, modulating EC Background-Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. Methods and Results-In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Conclusions-To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. 10 In particular, pericytes that are found along arterioles and capillaries express different degrees...

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“…It has recently been confirmed that EndMT is involved in CVDs such as PAH [22,23] and AS [3,4]. TGF-β1, a special multifunctional cytokine involved in the physiological and pathophysiological processes of the cardiovascular system, has been found to inhibit the vascular EC phenotype due to the disruption of endothelial intercellular junctions and the loss of apical-basolateral polarity [5,24].…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells

Feng

Zhang²,

Jackson³

et al. 2017

Cardiology

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Objective: Transforming growth factor β1 (TGF-β1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-β1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-β1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-β1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-β1-induced EndMT in human coronary artery ECs (HCAECs). Methods and Results: The HCAECs were treated with TGF-β1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-β1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-β1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-β1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-β1-induced EndMT. Conclusions: Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-β1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.

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Endothelial Fate Mapping in Mice With Pulmonary Hypertension

Cited by 80 publications

References 41 publications

SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification

SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells

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