Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension

Dai, Zhi; Zhu, Maggie M.; Peng, Yi; Jin, Hua; Machireddy, Narsa; Qian, Zhijian; Zhang, Xianming; Zhao, You Yang

doi:10.1164/rccm.201709-1835oc

Cited by 123 publications

(167 citation statements)

References 54 publications

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“…A previous study has also revealed that PI3Kα signaling via PDK1/AKT could mediate FGF2-induced FOXM1 upregulation in lung fibroblasts (32). Furthermore, FOXM1 signaling mediated vascular remodeling and pulmonary hypertension, as previously reported (27). Collectively, these studies indicated that PI3K/AKT and MEK/ERK pathways and FOXM1 may serve as potential post-receptor signaling pathways that mediate the profibrotic effect of CXCL12 in lung fibroblasts.…”

Section: Discussionsupporting

confidence: 72%

“…Multiple cell types can express CXCR4/CXCL12 in lung tissues (especially in fibrotic lungs), including fibroblasts, epithelial cells, vascular endothelial cells and some inflammatory cells (26)(27)(28)(29). As previously reported, a major population of CXCR4+ cells was localized close to the fibroblastic foci in lung tissue sections from patients with IPF (28,29).…”

Section: Discussionsupporting

confidence: 65%

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The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

Geng

et al. 2020

Exp Ther Med

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12 (CXCR4/CXCL12) axis has been implicated in the pathogenesis of pulmonary fibrosis. However, the mechanisms governing this remain to be determined. The current study demonstrated that human lung fibroblasts (HLFs) exhibit high CXCL12 expression and also exhibit high expression of its corresponding receptor CXCR4. Exogenous CXCL12 was revealed to significantly promote the migration and proliferation of HLFs, and potentiate CXCR4 expression. These effects were demonstrated to be inhibited by AMD3100, which is an antagonist of CXCR4. Lung and bronchoalveolar lavage fluid CXCR4 and CXCL12 expression was upregulated by in vivo bleomycin administration, which was partially inhibited by pre-treatment with AMD3100. AMD3100 also reduced lung collagen content in the bleomycin model. Inhibiting CXCR4 was indicated to ameliorate the lung compliance and resistance of pulmonary fibrosis. In conclusion, the results of the present study suggested that autocrine CXCR4/CXCL12 axis is an important mechanism underlying the pathogenesis of idiopathic pulmonary fibrosis, and may serve as a potential therapeutic target that can be used in the treatment of pulmonary disease.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 65%

The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

Geng

et al. 2020

Exp Ther Med

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“…; Dai et al . ). PH development is often associated with early and persistent perivascular inflammation in animal models of PH (Li et al .…”

Section: Introductionmentioning

confidence: 97%

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

Zhang

Laux

et al. 2018

The Journal of Physiology

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Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets.

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“…Findings from studies have "caught up" with this approach. With promising strategies under investigation to interrupt the proliferative, neoplastic-like nature of the disease, 1,22 patients and PAH care providers can hope to see continued improvement in outcome, perhaps hopedfor eradication of this disease.…”

Section: Summary and Thoughtsmentioning

confidence: 99%

Combination Therapy in Pulmonary Arterial Hypertension: Gleaning a Practical Approach from the Randomized Trials

Booth

2019

Int J Angiol

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In the past decade, combination therapy in pulmonary arterial hypertension (PAH) has evolved from something PAH practitioners felt almost compelled to do, notwithstanding the absence of data, to a strategy proven by well-conducted randomized clinical trials. Whereas in the past, PAH treatment was limited to parenteral epoprostenol; today multiple drugs administrable either parenterally, inhaled, or orally have expanded the options for treating PAH patients. The SERIPHIN, AMBITION, and GRIPHON trials and emerging findings in FREEDOM-EV confirm the validity of a combined-therapy approach. Data from these trials in which either combined therapy was planned or an agent was added to background therapy have demonstrated significant reduction in the progression of disease and are on the cusp of demonstrating survival benefit. Combination therapy may be started simultaneously in some cases, but in many cases a stepped approach to initiating a second, or third, agent is better tolerated. Trials of all the specific combinations of drugs may not be possible, but a continuing trend toward treating PAH with multiple agents is likely. Currently, Food and Drug Administration-approved agents are predominantly pulmonary vasodilators acting through different pathways, with minimal impact on progression of the proliferative pulmonary arteriopathy that is the key pathologic finding in PAH. It is to be hoped that treatment strategies that result in halting progression and substantial reversal of pulmonary arteriolar obstruction will soon be discovered and available.

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Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension

Abstract: Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation, which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of idiopathic PAH.

Cited by 123 publications

References 54 publications

The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

Combination Therapy in Pulmonary Arterial Hypertension: Gleaning a Practical Approach from the Randomized Trials

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