Regulation and role of endoglin in cholesterol‐induced endothelial and vascular dysfunction
            <i>in vivo</i>
            and
            <i>in vitro</i>

Vicen, Matej; Vitverová, Barbora; Havelek, Radim; Blazickova, Katerina; Macháček, Miloslav; Rathouska, Jana; Najmanová, Iveta; Doleželová, Eva; Prašnická, Alena; Sternak, Magdalena; Bernabeu, Carmelo; Nachtigal, Petr

doi:10.1096/fj.201802245r

Cited by 22 publications

(29 citation statements)

References 60 publications

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“…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%

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

Gallardo-Vara

Gamella-Pozuelo

Pérez-Roque

et al. 2020

Cells

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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.

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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

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“…Treatment of human umbilical vein endothelial cells (HUVEC) with 7KC results in increased expression of the cell adhesion molecules E-selectin, ICAM-1 and VCAM-1, and increased interactions between the endothelial cells and human monocytic THP-1 cells (Tani et al 2018 ). 7KC also increases the expression of endoglin, resulting in increased adhesion and transmigration of monocytes across human aortic endothelial cells (HAECs) (Vicen et al 2019 ). 7KC damages endothelial cells and increases the expression and release of clotting protein, von Willebrand factor (W. Li et al 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of Ergothioneine on 7-Ketocholesterol-Induced Endothelial Injury

et al. 2020

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Ergothioneine (ET) is a naturally occurring antioxidant that is synthesized by non-yeast fungi and certain bacteria. ET is not synthesized by animals, including humans, but is avidly taken up from the diet, especially from mushrooms. In the current study, we elucidated the effect of ET on the hCMEC/D3 human brain endothelial cell line. Endothelial cells are exposed to high levels of the cholesterol oxidation product, 7-ketocholesterol (7KC), in patients with cardiovascular disease and diabetes, and this process is thought to mediate pathological inflammation. 7KC induces a dose-dependent loss of cell viability and an increase in apoptosis and necrosis in the endothelial cells. A relocalization of the tight junction proteins, zonula occludens-1 (ZO-1) and claudin-5, towards the nucleus of the cells was also observed. These effects were significantly attenuated by ET. In addition, 7KC induces marked increases in the mRNA expression of pro-inflammatory cytokines, IL-1β IL-6, IL-8, TNF-α and cyclooxygenase-2 (COX2), as well as COX2 enzymatic activity, and these were significantly reduced by ET. Moreover, the cytoprotective and anti-inflammatory effects of ET were significantly reduced by co-incubation with an inhibitor of the ET transporter, OCTN1 (VHCL). This shows that ET needs to enter the endothelial cells to have a protective effect and is unlikely to act via extracellular neutralizing of 7KC. The protective effect on inflammation in brain endothelial cells suggests that ET might be useful as a nutraceutical for the prevention or management of neurovascular diseases, such as stroke and vascular dementia. Moreover, the ability of ET to cross the blood-brain barrier could point to its usefulness in combatting 7KC that is produced in the CNS during neuroinflammation, e.g. after excitotoxicity, in chronic neurodegenerative diseases, and possibly COVID-19-related neurologic complications.

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“…On the other hand, endoglin modulates ALK-1 ligand binding and signalling. Hypercholesterolemia alters endoglin expression and signalling, causing endothelial or vascular dysfunction before the initiation of atherosclerotic lesions 45 . All these findings suggest the participation of the endothelial receptors ALK1 and endoglin in the regulation of atherosclerosis, mainly exerting an antiatherogenic effect.…”

Section: Discussionmentioning

confidence: 99%

Association of Alk1 and Endoglin Polymorphisms with Cardiovascular Damage

Garzon-Martinez

Perretta-Tejedor

Gómez‐Marcos

et al. 2020

Sci Rep

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Cardiovascular diseases are associated to risk factors as obesity, hypertension and diabetes. The transforming growth factor-β1 receptors ALK1 and endoglin regulate blood pressure and vascular homeostasis. However, no studies relate the association of ALK1 and endoglin polymorphisms with cardiovascular risk factors. We analysed the predictive value of the ALK1 and endoglin polymorphisms on cardiovascular target organ damage in hypertensive and diabetic patients in 379 subjects with or without hypertension and diabetes in a Primary Care setting. The ALK1 rs2071219 polymorphism (AA genotype) is associated with a lower presence of diabetic retinopathy and with the absence of altered basal glycaemia. Being carrier of the ALK1 rs3847859 polymorphism (G allele) is associated with lower basal heart rate and with higher LDL-cholesterol levels. The endoglin rs3739817 polymorphism (AA genotype) is associated with higher levels of LDL-cholesterol, and being carrier of the endoglin rs10987759 polymorphism (C allele) is associated with higher haemoglobin levels and with an increased heart rate. Summarizing, several ALK1 and endoglin gene polymorphisms increase the risk of cardiovascular events. The analysis of these polymorphisms in populations at risk, in combination with the determination of other parameters and biomarkers, could implement the diagnosis and prognosis of susceptibility to cardiovascular damage.

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Regulation and role of endoglin in cholesterol‐induced endothelial and vascular dysfunction in vivo and in vitro

Cited by 22 publications

References 60 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

Effect of Ergothioneine on 7-Ketocholesterol-Induced Endothelial Injury

Association of Alk1 and Endoglin Polymorphisms with Cardiovascular Damage

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