Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta

Vitverová, Barbora; Blazickova, Katerina; Najmanová, Iveta; Vicen, Matej; Hyspler, R.; Doleželová, Eva; Němečková, Ivana; Tebbens, Jurjen Duintjer; Bernabeu, Carmelo; Pericacho, Miguel; Nachtigal, Petr

doi:10.1016/j.atherosclerosis.2018.02.008

Cited by 31 publications

(39 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, it has been reported that sEng contributes to endothelial dysfunction. Thus, sEng synergizes with hypercholesterolemia to aggravate endothelial and vessel wall dysfunction in vivo [43,45] and shows pro-inflammatory activity via nuclear factor-kappa B (NFkB) and interleukin 6 (IL6) in human endothelial cells in vitro [78]. Furthermore, exosomes from preeclamptic women induced vascular dysfunction by delivering sEng to endothelial cells [18].…”

Section: Discussionmentioning

confidence: 99%

“…If left untreated, preeclampsia can lead to serious, even fatal, complications for both mother and baby [41,42]. Noteworthy, several lines of evidence support a pathogenic role of sEng in cardiovascular conditions and diseases, including hypertension, endothelial dysfunction, anti-angiogenic activity, increased vascular permeability, vascular remodeling, and inflammation-associated leukocyte adhesion and transmigration [14,15,33,34,[42][43][44][45].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng + ) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng + mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng + mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this context, elucidating novel mechanisms of MΦ polarization may lead to a better understanding of their roles in vascular inflammation. In this manuscript, we report a new link between pro-inflammatory GM-MΦ and endothelial cells, by which GM-MΦ-derived MMP-12 targets membrane bound endothelial endoglin, leading to the release of sEng, a soluble protein with pro-inflammatory properties and the potential to promote endothelial dysfunction in combination with hypercholesterolemia [55]. Our results suggest that there is a direct and synergic effect of both MMP-12 and sEng in the context of the GM-MΦ/pro-inflammatory macrophage response (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

“…Shedding of the ectodomain of endoglin can be triggered by inflammation, tumor necrosis factor α (TNF-α), endothelial injury, or anti-endoglin antibodies [47,48,49,50,51]. Of note, sEng (i) displays pro-inflammatory activity via nuclear factor-kappa B (NFκB) and interleukin 6 (IL6) in human endothelial cells [52]; (ii) shows antiangiogenic activity and increased vascular permeability in vitro and in vivo [40,51,53]; (iii) modulates inflammation-associated monocyte adhesion and transmigration [13]; (iv) contributes to endothelial dysfunction, as shown in transgenic animals overexpressing human sEng [54,55]; and (v) regulates vascular development and arteriovenous malformations by modulating angiogenesis [47]. Therefore, identification of the mechanisms responsible for the generation of sEng in the inflammatory context may provide novel therapeutic targets for inflammation-related vascular pathologies.…”

Section: Introductionmentioning

confidence: 99%

MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

Aristorena

Gallardo-Vara

Vicen

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MΦ that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.

show abstract

“…It has been demonstrated that sEng levels increased both the expression of cell adhesion molecules and the number of rolling leukocytes, and that they impaired endothelial-dependent vascular function [ 116 ]. Moreover, sEng levels were higher in blood during endothelial injury or inflammation, but also in other vascular pathological conditions, such as atherosclerosis, hypercholesterolemia, hypertension, and T2D [ 117 ]. A clinical study conducted on 288 patients with T2D, hypertension, and healthy controls showed a significant correlation between endoglin and glycemia, glycated hemoglobin, systolic blood pressure, left ventricular hypertrophy and endothelial dysfunction [ 118 ].…”

Section: Oxidative Stress and Cellular Biomarkers For Prevention Amentioning

confidence: 99%

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

Scioli

Storti

D’Amico

et al. 2020

JCM

126

View full text Add to dashboard Cite

Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world’s leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of nitric oxide, with or without an imbalance between endothelium-derived contracting, and relaxing factors associated with a pro-inflammatory and prothrombotic status. Endothelial dysfunction-induced phenotypic changes include up-regulated expression of adhesion molecules and increased chemokine secretion, leukocyte adherence, cell permeability, low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. Inflammation-induced oxidative stress results in an increased accumulation of reactive oxygen species (ROS), mainly derived from mitochondria. Excessive ROS production causes oxidation of macromolecules inducing cell apoptosis mediated by cytochrome-c release. Oxidation of mitochondrial cardiolipin loosens cytochrome-c binding, thus, favoring its cytosolic release and activation of the apoptotic cascade. Oxidative stress increases vascular permeability, promotes leukocyte adhesion, and induces alterations in endothelial signal transduction and redox-regulated transcription factors. Identification of new endothelial dysfunction-related oxidative stress markers represents a research goal for better prevention and therapy of CVD. New-generation therapeutic approaches based on carriers, gene therapy, cardiolipin stabilizer, and enzyme inhibitors have proved useful in clinical practice to counteract endothelial dysfunction. Experimental studies are in continuous development to discover new personalized treatments. Gene regulatory mechanisms, implicated in endothelial dysfunction, represent potential new targets for developing drugs able to prevent and counteract CVD-related endothelial dysfunction. Nevertheless, many challenges remain to overcome before these technologies and personalized therapeutic strategies can be used in CVD management.

show abstract

Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta

Cited by 31 publications

References 36 publications

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

Contact Info

Product

Resources

About