Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-/ALK1 signal transduction. EMBO J. 23, 4018-4028

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
The EMBO Journal (Impact Factor: 10.43). 11/2004; 23(20):4018-28. DOI: 10.1038/sj.emboj.7600386
Source: PubMed


Endoglin is a transmembrane accessory receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells in culture and on angiogenic blood vessels in vivo. Endoglin, as well as other TGF-beta signalling components, is essential during angiogenesis. Mutations in endoglin and activin receptor-like kinase 1 (ALK1), an endothelial specific TGF-beta type I receptor, have been linked to the vascular disorder, hereditary haemorrhagic telangiectasia. However, the function of endoglin in TGF-beta/ALK signalling has remained unclear. Here we report that endoglin is required for efficient TGF-beta/ALK1 signalling, which indirectly inhibits TGF-beta/ALK5 signalling. Endothelial cells lacking endoglin do not grow because TGF-beta/ALK1 signalling is reduced and TGF-beta/ALK5 signalling is increased. Surviving cells adapt to this imbalance by downregulating ALK5 expression in order to proliferate. The ability of endoglin to promote ALK1 signalling also explains why ectopic endoglin expression in endothelial cells promotes proliferation and blocks TGF-beta-induced growth arrest by indirectly reducing TGF-beta/ALK5 signalling. Our results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation.

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Available from: Leon Jonker, Feb 26, 2014
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    • "This may be explained, at least in part, by endoglin-mediated increase in TGF-β-induced smad1,5,8 phosphorylation. TGF-β regulates cell proliferation, differentiation , migration, synthesis of the extracellular matrix[32,33]and promotes endothelial cell survival by activating ALK1/Smad 1/5/8 signalling[15,34]. Interestingly, a weak stimulatory effect was also observed in the absence of exogenous TGF-β, likely to result from the effects induced by other components of EMPs. "
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    ABSTRACT: Increased circulating levels of endoglin + endothelial microparticles (EMPs) have been identified in several cardiovascular disorders, related to severity. Endoglin is an auxilary receptor for transforming growth factor β (TGF-β) important in the regulation of vascular structure. We quantified the number of microparticles in plasma of six patients with chronic thromboembolic pulmonary hypertension (CTEPH) and age- and sex-matched pulmonary embolic (PE) and healthy controls and investigated the role of microparticle endoglin in the regulation of pulmonary endothelial function in vitro. Results show significantly increased levels of endoglin + EMPs in CTEPH plasma, compared to healthy and disease controls. Co-culture of human pulmonary endothelial cells with CTEPH microparticles increased intracellular levels of endoglin and enhanced TGF-β-induced angiogenesis and Smad1,5,8 phosphorylation in cells, without affecting BMPRII expression. In an in vitro model, we generated endothelium-derived MPs with enforced membrane localization of endoglin. Co-culture of these MPs with endothelial cells increased cellular endoglin content, improved cell survival and stimulated angiogenesis in a manner similar to the effects induced by overexpressed protein. Increased generation of endoglin + EMPs in CTEPH is likely to represent a protective mechanism supporting endothelial cell survival and angiogenesis, set to counteract the effects of vascular occlusion and endothelial damage.
    Full-text · Article · Dec 2016 · Journal of Biomedical Science
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    • "As endoglin and ALK1 proteins are predominantly expressed in endothelial cells, these are primary cellular targets of the disease. Thus, HHT manifestations are caused by a disturbance in the TGF-β signaling pathway (Attisano and Wrana, 2000; Goumans et al., 2002; Lebrin et al., 2004). Protein expression studies have shown that endoglin and ALK1 haploinsufficiency, by mutations that cause loss of function, is the underlying cause of HHT (Pece-Barbara et al., 1999). "
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    ABSTRACT: Hereditary haemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is predominantly caused by mutations in ENG and ACVRL1, which are part of the transforming growth factor beta (TGF-β) signalling pathway. HHT is characterized by the presence of mucocutaneous telangiectases and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anaemia. The clinical manifestations of HHT are extremely variable, even within family members, and the exact mechanism of how endoglin and ALK1 haploinsufficiency leads to HHT manifestations remains to be identified. The purpose of this study was to detect significantly differentially regulated genes in HHT, and try to elucidate the pathways and regulatory mechanisms occurring in the affected tissue of HHT patients, in order to further characterize this disorder and hypothesize on how telangiectases develop. By microarray technology (Agilent G3 Human GE 8x60), we performed global gene expression profiling of mRNA transcripts from HHT nasal telangiectasial (n=40) and non-telangiectasial (n=40) tissue using a paired design. Comparing HHT telangiectasial and non-telangiectasial tissue, significantly differentially expressed genes were detected using a paired t-test. Gene set analysis was performed using GSA-SNP. In the group of ENG mutation carriers, we detected 67 differentially expressed mRNAs, of which 62 were down regulated in the telangiectasial tissue. Gene set analysis identified the gene ontology (GO) terms vasculogenesis, TGF-β signalling, and Wnt signalling as differentially expressed in HHT1. Altered Wnt signalling might be related to HHT pathogenesis and a greater understanding of this may lead to the discovery of therapeutic targets in HHT. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Microvascular Research
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    • "The expression of endoglin (CD105), an endothelial-specific coreceptor for TGF-b, was reported to increase after anti-VEGF antibody treatment in a pancreatic cancer model (Bockhorn et al., 2003). Endoglin expression is upregulated during tumor angiogenesis and in proliferating EC (Duff et al., 2003), and it functions in facilitating TGF-b/ALK1 signaling (Lebrin et al., 2004; van Meeteren et al., 2012) as well as VEGF signaling (Liu et al., 2014b). Different studies indicate that endoglin is essential for angiogenesis (Bourdeau et al., 1999; Duff et al., 2003). "
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    ABSTRACT: The concept of antiangiogenic therapy in cancer treatment has led to the approval of different agents, most of them targeting the well known vascular endothelial growth factor pathway. Despite promising results in preclinical studies, the efficacy of antiangiogenic therapy in the clinical setting remains limited. Recently, awareness has emerged on resistance to antiangiogenic therapies. It has become apparent that the intricate complex interplay between tumors and stromal cells, including endothelial cells and associated mural cells, allows for escape mechanisms to arise that counteract the effects of these targeted therapeutics. Here, we review and discuss known and novel mechanisms that contribute to resistance against antiangiogenic therapy and provide an outlook to possible improvements in therapeutic approaches.
    Full-text · Article · Mar 2015 · Pharmacological Reviews
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