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Transforming Growth Factor-β/Smad Signaling in Myocardial Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Claudio Humeres, Nikolaos G. Frangogiannis
The balance between downstream activation of the ALK5-Smad2/3 and ALK1-Smad1/5 cascades is regulated through interactions between TGF-β receptors and “accessory receptors”3. Endoglin acts as an accessory protein for TGF-β signaling predominantly in endothelial cells and in activated fibroblasts, negatively regulating ALK5-Smad2/3 responses while enhancing ALK1-Smad1/5/8 signaling18,19,20. Betaglycan, a transmembrane glycoprotein that serves as a co-receptor, can either activate or inhibit TGF-β signaling responses, depending on its expression levels, and on contextual factors21,22. Although betaglycan and endoglin are the best-studied TGF-β co-receptors, a growing list of other transmembrane molecules (such as CD44 and neuropilin-1)23,24,25 may also modulate TGF-β responses. In most cases, these coreceptors are promiscuous and interact with many other growth factors; thus, their role in modulating TGF-β responses in vivo remains unclear.
Hypertension and pre-eclampsia
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
Soluble Flt1 (sFlt1) and soluble endoglin (sEng), secreted by the placenta in excess in pre-eclampsia, are anti-angiogenic factors producing systemic endothelial dysfunction by antagonizing VEGF and TGF-β1 signalling. sFlt1 is secreted into the circulation where it binds and antagonizes VEGF and placental growth factor (PlGF).
Nidus or no nidus: Is it a crucial issue for diagnostic assessment of arteriovenous malformations?
Published in Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic, Vascular Malformations, 2019
Endoglin is a TGF-β coreceptor that is necessary for angiogenesis. Endoglin null embryos exhibit a loss of arteriovenous identity and defective vSMC recruitment. Examination of endoglin null embryos revealed ectopic arterial expression of the venous-specific marker COUP-TFII when endoglin reexpression in endothelial cells restored normal COUP-TFII expression. These findings suggest that endoglin plays distinct and cell-autonomous roles in vSMC recruitment and arteriovenous specification via COUP-TFII in angiogenesis.
Bone morphogenetic protein (BMP)9 in cancer development: mechanistic, diagnostic, and therapeutic approaches?
Published in Journal of Drug Targeting, 2023
Ali G. Alkhathami, Mustafa Ryadh Abdullah, Muhjaha Ahmed, Hanan Hassan Ahmed, Sarab W. Alwash, Zahra Muhammed Mahdi, Fahad Alsaikhan, Ayed A. Dera
Another study regarding the BMP9 neutralisation approach is based on endoglin. In endothelial cells and endothelial colony-forming cells, endoglin is predominantly expressed as a type I transmembrane glycoprotein. It is also known as an essential co-receptor for TGFβ, functioning an essential role in angiogenesis [75]. There is increasing evidence in which a cross-link between BMP9 and membrane-bound endoglin has been observed. Based on this observation it was designed a chimaera composed of endoglin extracellular domain ECD fused to Fc (EngECD-Fc) to assess its interaction with BMP9 to modulate its function. Data have shown that Endoglin ECD binds BMP9 selectively and strongly at physiological temperatures. In terms of biological activity, EngECD-Fc significantly decreased VEGF-induced vasculation and vessel formation in vivo chick chorioallantoic membrane assay. Moreover, murine EngECD-Fc functioned as an anti-angiogenic factor by reducing vessel sprouting in FGF/VEGF-induced tumour angiogenesis and decreased tumour burden in C26 colon carcinoma-bearing mice, highlighting the efficacy of EngECD-Fc as a potential anti-angiogenic agent [76].
Targeting BMPR-II in pulmonary arterial hypertension: a case of Hercules versus the Hydra?
Published in Expert Opinion on Therapeutic Targets, 2022
M. Martin VandenBroek, Sofia I. Skebo, Mark L Ormiston
With this success, Sotatercept is poised to transform the PAH therapeutic landscape by becoming the first approved therapy that directly targets imbalanced TGFβ/Activin/BMP superfamily signaling and thereby addresses the cellular and genetic underpinnings of the disease. However, this success is not without its limitations. Increased hemoglobin was observed in 11% of patients receiving Sotatercept in the PULSAR trial [18], with this number increasing to 14% in the open-label extension [19]. This dose-limiting effect on erythropoiesis was accompanied by the more concerning development of telangiectasias in 11 of the 104 Sotatercept-treated patients in the open-label extension [19]. Importantly, similar signs of vascular instability have been reported in clinical trials for both ActRIIB-Fc (Ramatercept) and Alk1-Fc (Dalantercept) ligand traps [22,23]. These telangectasias, which are evocative of the arteriovenous malformations seen in individuals with hereditary hemorrhagic telangiectasia (HHT)-associated mutations in the genes encoding Alk1 and Endoglin, are generally attributable to the sequestration of BMP9 and/or BMP10 and a resultant loss of the stabilizing effects of these ligands on the endothelium.
Circulating s-Endoglin concentrations in non-obese patients with gestational diabetes mellitus
Published in Journal of Obstetrics and Gynaecology, 2022
Sümeyra Nergiz Avcıoğlu, Selda Demircan Sezer, Sündüz Özlem Altınkaya
Hyperinsulinemia, insulin resistance, hyperglycaemia and dyslipidemia independently contribute to endothelial dysfunction through different mechanisms. It was demonstrated that s-Endoglin impairs capillary formation and endothelial cell proliferation (Blazquez-Medela et al). Additionally, the administration of s-Endoglin to mice induces an increase in arterial pressure by increasing vascular resistance and it seems also to be a regulator of vascular tone. S-Endoglin seems to impair endothelial function (Blazquez-Medela et al. 2010; Anık et al. 2020). Endothelial dysfunction and angiogenesis are also known to be major pathological pathways of diabetic complications (Di Marco et al. 2008). Emeksiz et al. determined that in adolescents with T1DM, s-endoglin concentrations may increase in parallel to the deterioration in endothelial function before subclinical structural vascular alterations become evident (Emeksiz et al. 2016). Similarly, we suggest that the higher concentrations of s-Endoglin in the present study and the positive correlation with insulin resistance markers in patients with GDM may indicate that s-Endoglin levels may cause endothelial dysfunction of the placenta. Also, endothelial dysfunction caused by high s-Endoglin levels may be an important risk factor for diabetic complications such as nephropathy, neuropathy and retinopathy in patients further on in life.