Article

Novel biochemical pathways of endoglin in vascular cell physiology

Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas (CSIC), 28040 Madrid, Spain.
Journal of Cellular Biochemistry (Impact Factor: 3.26). 12/2007; 102(6):1375-88. DOI: 10.1002/jcb.21594
Source: PubMed

ABSTRACT

The broad role of the transforming growth factor beta (TGFbeta) signaling pathway in vascular development, homeostasis, and repair is well appreciated. Endoglin is emerging as a novel, complex, and poorly understood regulatory component of the TGFbeta receptor complex, whose importance is underscored by its recognition as the site of mutations causing hereditary hemorrhagic telangiectasia (HHT) [McAllister et al., 1994]. Extensive analyses of endoglin function in normal developmental mouse models [Bourdeau et al., 1999; Li et al., 1999; Arthur et al., 2000] and in HHT animal models [Bourdeau et al., 2000; Torsney et al., 2003] exemplify the importance of understanding endoglin's biochemical functions. However, novel mechanisms underlying the regulation of these pathways continue to emerge. These mechanisms include modification of TGFbeta receptor signaling at the ligand and receptor activation level, direct effects of endoglin on cell adhesion and migration, and emerging roles for endoglin in the determination of stem cell fate and tissue patterning. The purpose of this review is to highlight the cellular and molecular studies that underscore the central role of endoglin in vascular development and disease.

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Available from: Carmelo Bernabeu, Mar 13, 2014
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    • "These data not only show that expression of both endoglin isoforms in monocytic cells reduces their adhesion to the extracellular matrix, but that it also impairs their trafficking, which necessarily involves cell adhesion. Supporting this interpretation, studies in different cell types have shown that overexpression of either Lendoglin or S-endoglin leads to reduced cellular migration (Guerrero-Esteo et al., 1999; Liu et al., 2002; Conley et al., 2004; Bernabeu et al., 2007). Furthermore, the upregulation of Sendoglin during macrophage senescence is in line with the decreased migration of myeloid cells, as well as the impaired anti-inflammatory response, observed during aging (Shaw et al., 2010; Li, 2013). "
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    ABSTRACT: Endoglin plays a crucial role in physiopathological processes such as Hereditary Hemorrhagic Telangiectasia (HHT), preeclampsia or cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of endoglin have been reported, L-endoglin and S-endoglin. While L-endoglin is the predominant variant, an increased expression of the S-endoglin isoform during senescence of the myeloid lineage, in human and murine models, was observed. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-endoglin and S-endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-endoglin expression led to decreased cellular proliferation and survival response to GM-CSF-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggest a non-redundant role for each endoglin isoform in monocyte biology. In addition, we find that S-endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.
    Preview · Article · Apr 2014 · Journal of Cell Science
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    • "We found that mASCs expressed only the CD105L isoform. CD105L inhibits ALK5/smad3 activation while it promotes ALK1/smad1 and ALK5/smad2 activation [30,57–59]. TGF-β-mediated activation of smad2 has been shown to inhibit both adipogenesis [60] and osteogenesis [30]. "
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    ABSTRACT: Administration of in vitro expanded mesenchymal stromal cells (MSCs) represents a promising therapy for regenerative medicine and autoimmunity. Both mouse and human MSCs ameliorate autoimmune disease in syn-, allo- and xenogeneic settings. However, MSC preparations are heterogeneous which impairs their therapeutic efficacy and endorses variability between experiments. This heterogeneity has also been a main hurdle in translating experimental MSC data from mouse models to human patients. The objective of the present manuscript has been to further characterize murine MSCs (mMSCs) with the aim of designing more efficient and specific MSC-based therapies. We have found that mMSCs are heterogeneous for endoglin (CD105) expression and that this heterogeneity is not due to different stages of MSC differentiation. CD105 is induced on a subpopulation of mMSCs early upon in vitro culture giving rise to CD105(+) and CD105(-) MSCs. CD105(+) and CD105(-) mMSCs represent independent subpopulations that maintain their properties upon several passages. CD105 expression on CD105(+) mMSCs was affected by passage number and cell confluency while CD105(-) mMSCs remained negative. The CD105(+) and CD105(-) mMSC subpopulations had similar growth potential and expressed almost identical mMSC markers (CD29(+)CD44(+)Sca1 (+) MHC-I(+) and CD45(-)CD11b(-)CD31(-)) but varied in their differentiation and immunoregulatory properties. Interestingly, CD105(-) mMSCs were more prone to differentiate into adipocytes and osteocytes and suppressed the proliferation of CD4(+) T cells more efficiently compared to CD105(+) mMSCs. Based on these studies we propose to redefine the phenotype of mMSCs based on CD105 expression.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Eng has crucial functions in angiogenesis and inflammation (Bernabeu et al., 2007; ten Dijke et al., 2008; López-Novoa and Bernabéu, 2010), two processes intimately linked to wound healing (Valluru et al., 2011a). In this work, we show that skin wound healing is delayed in Eng-deficient mice, in particular at 2–8 days after the injury. "
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    ABSTRACT: Endoglin is transmembrane glycoprotein mainly expressed in endothelial cells but also present in the epidermis and skin appendages. To address the role of endoglin in cutaneous wound healing, we compared the kinetics of re-epithelialization in endoglin heterozygous null (Eng(+/-)) mice and their normal littermates (Eng(+/+)) following skin wounds. The wound area was significantly larger in Eng(+/-) than Eng(+/+)mice from 2-8 days after injury; overall wound closure was delayed by 1 to 2 days. In Eng(+/-) mice keratinocytes at the wound edges exhibited impaired proliferation but were more migratory, as shown by their elongated morphology and increased keratin 17 expression. Inhibition of nitric oxide (NO) synthesis delayed healing in Eng(+/+) but not in Eng(+/-) mice. Administration of the NO donor LA-803 accelerated wound closure in Eng(+/-) mice with no effect in normal littermates. The acute stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated endoglin expression in mouse epidermal keratinocytes in vivo and in vitro associated with hyperproliferation. Likewise, the skin of Eng+/- mice failed to mount a hyperplastic response to acute stimulation with TPA. These results demonstrate an important involvement of endoglin in wound healing that is associated with NO bioavailability.Journal of Investigative Dermatology accepted article preview online, 13 June 2013; doi:10.1038/jid.2013.263.
    Full-text · Article · Jun 2013 · Journal of Investigative Dermatology
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