Role of soluble endoglin in BMP9 signaling

Lawera, Aleksandra; Tong, Zhen; Thorikay, Midory; Redgrave, Rachael; Cai, Jie; Dinther, Maarten van; Morrell, Nicholas W.; Afink, Gijs B.; Charnock-Jones, D. Stephen; Arthur, Helen M.; Dijke, Peter ten; Li, Wei

doi:10.1073/pnas.1816661116

Cited by 69 publications

(82 citation statements)

References 50 publications

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“…Also, a number of potential novel interactors of sEng located in the nucleus have been recently identified [68]. Furthermore, sEng bound to BMP9 is able to intracellularly signal via membrane-bound endoglin in endothelial cells, rather than being an inhibitory ligand trap [24]. Whether the sEng-dependent regulation of BMP4 gene expression is mediated by the downstream TGF-β/BMP signaling pathways, a yet-to-discover function of sEng, or both, remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…The OR of endoglin binds with high affinity to members of the TGF-β family, namely bone morphogenetic protein 9 (BMP9) and BMP10 [21][22][23]. Interestingly, rather than being an inhibitory ligand trap, the sEng/BMP9 complex is able to signal via membrane-bound endoglin in endothelial cells [24]. Noteworthy, dysregulated BMP signaling has been linked to vascular diseases, including HHT, pulmonary hypertension, and atherosclerosis, likely through endothelial dysfunction [25].…”

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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“…Although endothelial loss of ENG or ALK1 lead to AVMs in preclinical models, the phenotype of ALK1-iKO e mutants is more severe than that of Eng-iKO e mutants [7]. This is likely because loss of ALK1, the signalling receptor, leads to elimination of this signalling pathway, whilst loss of ENG, the co-receptor, reduces the availability of ligand to the signalling receptor [3], thereby dampening rather than completely obliterating signal. In HHT patients however, the differences between HHT1 (ENG) and HHT2 (ALK1) clinical phenotypes are more complex and await a better understanding of the relative contribution of second hits and additional factors such as inflammation to fully unravel the etiology of this disease.…”

Section: Discussionmentioning

confidence: 99%

Arterial endoglin does not protect against arteriovenous malformations

Arthur

Singh

Phillips

2020

Preprint

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Keywords Arteriovenous malformationHereditary Haemorrhagic Telangiectasia Acvrl1Retinal angiogenesis Notch Acknowledgements This work was funded by the British Heart Foundation (RG/12/2/29416, PG/18/25/33587, PG/18/32/33760) and the Cookson Trust. We are grateful to Kristy Red-Horse for sharing the Apj-Cre-ERT2 mouse line. AbstractEndoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder Hereditary Haemorrhagic Telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. MethodsUsing the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following panendothelial or venous/capillary-specific ENG knockout. ResultsActivation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature.Conclusion Expression of ENG is not required in arterial ECs to protect against AVM formation.

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“…Some reports show that sENG is significantly higher in plasma from PE patients, but logistic regression analysis describes that sENG levels are independently associated with the development of PE [116]. A complex of sENG (monomer)/BMP9 has been detected in both PE patients and a control group, being slightly higher in the PE group [117]. Lawera and colleagues observed that binding of sENG to BMP9 does not inhibit BMP9 signaling [117].…”

Section: Preeclampsiamentioning

confidence: 99%

“…A complex of sENG (monomer)/BMP9 has been detected in both PE patients and a control group, being slightly higher in the PE group [117]. Lawera and colleagues observed that binding of sENG to BMP9 does not inhibit BMP9 signaling [117]. Moreover, the increased circulating sENG might rather direct BMP9 signaling via cell-surface ENG.…”

Section: Preeclampsiamentioning

confidence: 99%

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

2020

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Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

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Role of soluble endoglin in BMP9 signaling

Cited by 69 publications

References 50 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

Arterial endoglin does not protect against arteriovenous malformations

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

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