An update on the role of membrane and soluble endoglin in vascular homeostasis

1p.Peer reviewe

Alternative Splicing in Endothelial Senescence: Role of the TGF-β Co-Receptor Endoglin

No abstract available

The Splicing Factor SRSF1 as a Marker for Endothelial Senescence

Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of the endothelial cells (ECs) that line the lumen of blood vessels is the cellular basis for these age-dependent vascular pathologies, including atherosclerosis and hypertension. During their lifespan, ECs may reach a stage of senescence by two different pathways; a replicative one derived from their preprogrammed finite number of cell divisions; and one induced by stress stimuli. Also, certain physiological stimuli, such as transforming growth factor-β, are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine–arginine splicing factor 1 (SRSF1, or ASF/SF2) during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, which typically exhibits a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of EC senescence, regulating the expression of alternative isoforms of target genes such as endoglin (ENG), vascular endothelial growth factor A (VEGFA), tissue factor (T3), or lamin A (LMNA) that integrate in a common molecular senescence program

Endothelial and vascular function in mice overexpressing human soluble endoglin

1 p. Nemeckova, Ivana et al.This work was supported by grants from Czech Science foundation GACR number 15-24015S, the Grant Agency of Charles University in Prague (1284214/C and 1158413/C), Charles University in Prague (SVV/2014/260064), European Regional Development Fund under the Innovative Economy Program of the European Union (grant coordinated by JCET-UJ, No POIG.01.01.02-00-069/09), Ministerio de Economia y Competitividad of Spain (SAF2010-19222 and SAF2013-43421-R and SAF2010-1588), Junta de Castilla y Leon (GR100), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Red de Investigacion Cooperativa en Enfermedades Renales (RD12/0021/0032; REDINREN). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds. The Cardiovascular Phenotyping Unit of the University of Salamanca, including the telemetry equipment, was acquired with the support of the European Regional Development Funds (FEDER). Ministerio de Economia y Competitividad (BES-2008-005550). This work has been co-financed by the European Social Fund and the state budget of the Czech Republic (Project No. CZ.1.07/2.3.00/30.0061).Peer reviewe

Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1)

5 p.-2 fig.Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.This study was supported by grants from the Ministerio de Economia y Competitividad of Spain (SAF2010-19222 and SAF2013-43421-R to Carmelo Bernabeu; SAF2010-1588, SAF2013-45784-R, and RD12/0021/0032-REDINREN to José M. Lopez-Novoa).Peer reviewe

Método de detección de la Telangiectasia Hemorrágica Hereditaria

Método de detección de la Telangiectasia Hemorrágica Hereditaria. Método para la detección de la Telangiectasia Hemorrágica Hereditaria (HHT) que comprende el análisis in vitro de los productos de la expresión de los genes ENG o FLT1 Y ENG o ANGPT2 en muestras biológicas de pacientes y que, además, permite sub-clasificar las variantes HHT1 y HHT2 de la enfermedad. En particular, la presente invención se refiere a un kit para la detección molecular de HHT capaz de llevar a cabo la detección mencionada anteriormente.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)A1 Solicitud de patentes con informe sobre el estado de la técnic

Endoglin Regulates Cyclooxygenase-2 Expression and Activity

Jerkic, Mirjana[et alt.] 9 p.-8 fig.The endoglin heterozygous (Eng+/−) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng+/− mice and the potential interactions between the NO- and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E2 were observed in the Eng+/− mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Eng+/− but not in Eng+/+ mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with Nω-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng+/+ mice. Nω-nitro-l-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-β1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the Eng+/− miceThis work was supported by grants from Ministerio de Educacion y Ciencia (SAF2001/1701 to J.M.L.-N. and SAF2004–01390 to C.B.), Fondo de Investigación Sanitaria (PI020200 to C.B.), HHT Foundation International to C.B., and by the Heart and Stroke Foundation of Canada (T5016) to M.L. M.J. was supported by a Fellowship from Instituto Reina Sofía de Investigación Nefrológica. C.P.H.V. was supported by NIH grant #P2015555 from the National Center for Research ResourcesPeer reviewe

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction

33 p.-9 fig.-2 tab. Muñoz-Felix. J. M. et al.Transforming growth factor beta 1 (TGF-β1) is one of the most studied cytokines involved in renal tubulo¬interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-β1 actions in different biological processes, includ¬ing ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG+) and we have performed an UUO in S-ENG+ and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG+ mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG+ mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.This study has been supported by grants from Ministerio de Economía y Competitividad of Spain (SAF2013-43421-R to CB; and SAF2013-45784-R to JML-N), Junta de Castilla y León (GR100, JML-N), Institute Queen Sophie for Renal Research, Fundación Renal Íñigo Álvarez de Toledo, Madrid, Spain (0016¬002), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, CB) (ISCIII-CB06/07/0038) and Red de Investigación Cooperativa en Enfermedades Renales (REDINREN, JML-N) (R12/0021/ 0032). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds. BO and ENG are supported by fellowships from Ministerio de Economía y Competitividad (BES-2011-048968 and BES-2008-005550). JMMF, LPR and CC are supported by fellowships from Junta de Castilla y León and Fondo Social Europeo (EDU/1204/2010 and EDU/1083/2013).Peer reviewe

The role of endoglin in post-ischemic revascularization

60 p.-5 fig.-1 tab.Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by re-organizing pre-existing capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling pre-existing collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: i) endoglin expression is increased in vessels showing active angiogenesis/remodeling; ii) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and iii) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis, and collateral development) associated with post-ischemic revascularization.Peer reviewe

A role for the Tgf-β/Bmp co-receptor Endoglin in the molecular oscillator that regulates the hair follicle cycle.

The hair follicle is a biological oscillator that alternates growth, regression, and rest phases driven by the sequential activation of the proliferation/differentiation programs of resident stem cell populations. The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling, while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity. A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways. Here we have focused on the role of Endoglin (Eng), a key co-receptor for members of the Tgf-β/Bmp family of growth factors. Using an Eng haploinsufficient mouse model, we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches. We further report that β-catenin binds to the Eng promoter depending on Bmp signalling. Moreover, we show that β-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription. These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.pre-print1347 K