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Special Issue "Endoglin in Health and Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Lukas J.A.C. Hawinkels
Website
Guest Editor
Department of Gastroenterology-Hepatology, Leiden University Medical Center - LUMC, Leiden, The Netherlands
Interests: cancer-associated fibroblasts; colorectal cancer; endoglin; tumor microenvironment; angiogenesis; TGFbeta; tumor–stroma interactions
Prof. Marie-José Goumans
Website
Guest Editor
Laboratory for cardiovascular cell biology, Department of cell and chemical biology, Leiden University Medical Center - LUMC, The Netherlands
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Endoglin is a co-receptor for members of the transforming growth factor (TGF)-β family, and is known for its crucial role during developmental- and tumor angiogenesis. Extensive work has shown the important roles endoglin plays in modulating the TGF-β signaling pathway, thereby regulating endothelial cell proliferation, migration, and differentiation. Mutations in the endoglin gene (ENG) have been linked to the autosomal vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vessel abnormalities. In cancer, endoglin is extensively studied in relation to tumor angiogenesis. High endoglin levels have been related to poorer prognoses for patients with solid tumors. Consequently, therapies that interfere with the function of endoglin, like soluble endoglin ligand traps and neutralizing antibodies to endoglin, have been developed and (clinically) evaluated. Besides the important role for endoglin in regulating angiogenesis, recent work also shows a more widespread role for endoglin beyond the endothelium. Endoglin expression is also reported on epithelial (cancer) cells, cancer-associated fibroblasts, smooth muscle cells in pathological conditions, and cells of the innate- and adaptive immune system. This Special Issue will bring together the most recent work on endoglin in regulating angiogenesis, but also on its role in non-endothelial cells and the potential of endoglin targeting as a new treatment option in various diseases.

Dr. Lukas J.A.C. Hawinkels
Prof. Marie-José Goumans
Guest Editors

Manuscript Submission Information

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Keywords

  • endoglin
  • HHT
  • TRC105
  • angiogenesis
  • bone morphogenetic protein

Published Papers (4 papers)

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Research

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Open AccessArticle
Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities
Int. J. Mol. Sci. 2021, 22(1), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010165 - 26 Dec 2020
Abstract
Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical [...] Read more.
Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed. Full article
(This article belongs to the Special Issue Endoglin in Health and Disease)
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Open AccessArticle
Endoglin Promotes Myofibroblast Differentiation and Extracellular Matrix Production in Diabetic Nephropathy
Int. J. Mol. Sci. 2020, 21(20), 7713; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207713 - 18 Oct 2020
Abstract
Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and [...] Read more.
Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining (p < 0.001). Endoglin expression was also correlated with reduced eGFR (p = 0.001), increased creatinine (p < 0.01), increased systolic blood pressure (p < 0.05), hypertension (p < 0.05), and higher IFTA scores (p < 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or α-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker α-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-β1 stimulation upregulated SERPINE1, CTGF, and ACTA2 mRNA and α-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN. Full article
(This article belongs to the Special Issue Endoglin in Health and Disease)
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Review

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Open AccessReview
Endoglin Targeting: Lessons Learned and Questions That Remain
Int. J. Mol. Sci. 2021, 22(1), 147; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010147 - 25 Dec 2020
Abstract
Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high expression on tumor vessels and its correlation with poor survival in cancer patients led to the [...] Read more.
Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high expression on tumor vessels and its correlation with poor survival in cancer patients led to the exploration of endoglin as a therapeutic target for cancer. The endoglin neutralizing antibody TRC105 (Carotuximab®, Tracon Pharmaceuticals (San Diego, CA, USA) was subsequently tested in a wide variety of preclinical cancer models before being tested in phase I-III clinical studies in cancer patients as both a monotherapy and in combination with other chemotherapeutic and anti-angiogenic therapies. The combined data of these studies have revealed new insights into the role of endoglin in angiogenesis and its expression and functional role on other cells in the tumor microenvironment. In this review, we will summarize the preclinical work, clinical trials and biomarker studies of TRC105 and explore what these studies have enabled us to learn and what questions remain unanswered. Full article
(This article belongs to the Special Issue Endoglin in Health and Disease)
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Open AccessReview
Endoglin: An ‘Accessory’ Receptor Regulating Blood Cell Development and Inflammation
Int. J. Mol. Sci. 2020, 21(23), 9247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239247 - 03 Dec 2020
Abstract
Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling [...] Read more.
Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the ‘accessory’ receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages. Full article
(This article belongs to the Special Issue Endoglin in Health and Disease)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Endoglin and the hematopoietic system

Title: Endoglin in hepatocellular carcinoma

Title: Endoglin under the Spotlight of Cancer Treatment

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