Endothelial cells in the pathogenesis of pulmonary arterial hypertension

Evans, Colin E.; Cober, Nicholas D; Dai, Zhiyu; Stewart, Duncan J.; Zhao, Yan

doi:10.1183/13993003.03957-2020

Cited by 170 publications

(127 citation statements)

References 199 publications

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“…It is an important locus of critical regulatory nodes to retain the homeostasis of the (Gimbrone and García-Cardeña, 2016). Therefore, it is significant to point out that endothelial cell dysfunction is involved in many disease processes, including atherosclerosis, pulmonary arterial hypertension and sepsis (Gimbrone and García-Cardeña, 2016;Joffre et al, 2020;Evans et al, 2021). Here we focus on the involvement of SIRT6 in atherosclerosis and endothelial cell dysfunction.…”

Section: Sirt6 and Endothelial Dysfunctionmentioning

confidence: 99%

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

Liu

et al. 2021

Front. Cell Dev. Biol.

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SIRT6 belongs to the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Its function is similar to the Silent Information Regulator 2 (SIR2), which prolongs lifespan and regulates genomic stability, telomere integrity, transcription, and DNA repair. It has been demonstrated that increasing the sirtuin level through genetic manipulation extends the lifespan of yeast, nematodes and flies. Deficiency of SIRT6 induces chronic inflammation, autophagy disorder and telomere instability. Also, these cellular processes can lead to the occurrence and progression of cardiovascular diseases (CVDs), such as atherosclerosis, hypertrophic cardiomyopathy and heart failure. Herein, we discuss the implications of SIRT6 regulates multiple cellular processes in cell senescence and aging-related CVDs, and we summarize clinical application of SIRT6 agonists and possible therapeutic interventions in aging-related CVDs.

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Section: Sirt6 and Endothelial Dysfunctionmentioning

confidence: 99%

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…Healthy pulmonary vascular endothelial cells (PVECs) maintain vascular hemostasis via preserving vascular integrity, remaining vascular tone, and exhibiting an anti-inflammatory niche. Endothelial injury or dysfunction has been believed to the initial event during the development of PAH [6]. Dysfunctional PVECs produce many kinds of growth factors or angiocrine factors which sustains the pro-proliferative environment.…”

Section: Introductionmentioning

confidence: 99%

“…Both autocrine and paracrine signaling pathways are important to maintain vascular homeostasis and contribute to pathological angiogenesis [6]. PVECs from PAH patients exhibit increased production of growth factors, such as FGF2, IL-6, ET-1, TGF-beta, etc.…”

Section: Introductionmentioning

confidence: 99%

“…PVECs from PAH patients exhibit increased production of growth factors, such as FGF2, IL-6, ET-1, TGF-beta, etc. These factors promote PVECs/smooth muscle cells (SMCs)/fibroblasts proliferation and survival, stimulate SMCs vasoconstriction, and even recruit leukocytes [6]. For example, our previous studies demonstrated that PVECs from PAH patients or Egln1 Tie2Cre mice which develop spontaneous PH [7,8], secrete multiple angiocrine factors including CXCL12, PDGF-B, ET-1, and MIF, which induced the expression of proliferation specific transcriptional factor forkhead box M1 (FoxM1) and proliferation of SMCs.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension

Liu

Wang

Liao

et al. 2021

Preprint

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Endothelial autocrine signaling is essential to maintain vascular hemostasis. There is limited in-formation about the role of endothelial autocrine signaling in regulating severe pulmonary vas-cular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe PAH mouse model, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cells (PVECs) hyperproliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhib-ited hyperproliferative phenotype in coincident with upregulation of proliferation specific tran-scriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in culture human PVECs. Endo-thelial specific deletion of Cxcl12 (Egln1/Cxcl12Tie2 Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine sig-naling in regulating PVECs hyperproliferation and pulmonary vascular remodeling in PAH.

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“…When blood pressure continues to rise, the shear stress on the vessel wall can directly affect the vascular endothelial cells and cause mechanical damage, leading to endothelial cell dysfunction, even necrosis and exfoliation [9]. Hypertension can damage the endothelium, and likewise, damage to the endothelium can exacerbate an increase in blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Neohesperidin Protects Hypertension-induced Endothelial Injury by Intervening Oxidative Stress

Zhang¹,

Hui²,

Liu³

et al. 2021

Preprint

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Background: Currently, vascular endothelial damage caused by hypertension is one of the major health challenges facing countries around the world. Neohesperidin has been shown to play an important role in tumorigenesis and tumorigenesis, cardiac hypertrophy and remodeling, and oxidative stress. However, whether Nehesperidin plays an important role in endothelial injury induced by hypertension has not been clarified.Results: In this study, Angiotensin II was used to induce hypertension in mice. Blood pressure and vasoconstrictor function were measured, vascular thickness and fibrosis were detected by H&E and Masson tricolor staining, vascular inflammation was detected by immunofluorescence, oxidative stress was detected by DHE staining, and markers such as fibrosis, hypertrophy and oxidative stress were detected by qPCR. At the same time, we observed the effect of Nehesperidin on Ang II-induced HUVECs. The results showed that neohesperidin can significantly inhibit Ang II-induced hypertension, vascular thickness, fibrosis, oxidative stress and inflammation in vivo and in vitro. Conclusions: The results suggested that Nehesperidin could act as an antioxidant to significantly inhibit Ang II-induced hypertension and endothelial injury in HUVECs in mice by inhibiting oxidative stress response.

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Endothelial cells in the pathogenesis of pulmonary arterial hypertension

Cited by 170 publications

References 199 publications

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension

Neohesperidin Protects Hypertension-induced Endothelial Injury by Intervening Oxidative Stress

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