Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cells is mediated by endoglin.

Endoglin, a transforming growth factor ß (TGF-ß) receptor type III, is co-expressed with endothelial nitric oxide synthase (eNOS) in aortic endothelium in atherosclerotic plaques of mice. Interestingly, atorvastatin (ATV) is able to increase both endoglin and eNOS expression and reduce plaque size beyond its lipid lowering effects but by unknown mechanisms. We hypothesized whether inflammation modulates ATV-dependent induction of endoglin and eNOS expression in vitro in endothelial cells and whether ATV-induced eNOS expression is regulated via endoglin. After treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α, endoglin and eNOS protein expression was reduced, concomitantly with increased levels of cell surface VCAM-1 and soluble endoglin, as determined by flow cytometry, Western blot and ELISA analyses. By contrast, ATV treatment increased endoglin and eNOS protein expression, while preventing TNF-α-mediated downregulation of endoglin and eNOS protein levels. Moreover, suppression of endoglin using small interfering RNA (siRNA), but not inhibition of TGF-ß signaling with SB431542, abrogated ATV-induced eNOS expression. These results suggest that ATV treatment prevents inflammation-reduced endoglin and eNOS expression in endothelial cells and that ATV-induced eNOS expression strongly depends on the proper expression of endoglin in HUVECs. Possible implications of these findings might be reflected in pathological conditions characterized by reduced expression of endoglin and eNOS as for example in hereditary hemorrhagic telangiectasia or in other endothelial dysfunctions.

Membrane and soluble forms of endoglin in preeclampsia.

Preeclampsia is a disease of high incidence in pregnant women which complicates pregnancy and may lead to the death of mother and baby. Preeclampsia is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction. Although the causes of disease have not been elucidated, it has been reported that high levels of endoglin, a TGF-ß auxiliary co-receptor, and a soluble form of this protein, occur respectively in the placenta and plasma of women who develop the disease. In this review, the alterations in vasculogenesis and angiogenesis that occur during preeclampsia, the cellular and molecular mechanisms that lead to increased membrane bound endoglin expression and soluble endoglin release, including hypoxia and oxidative stress, and the possible pathogenic role of soluble endoglin in this disease have been analyzed.

Cannabis use and age at onset of psychosis: further evidence of interaction with COMT Val158Met polymorphism.

OBJECTIVE: To examine, in a sample of young psychiatric patients, (n = 157, mean age 17.01 years (SD = 3.6)) whether i) age at first cannabis use and age at emergence of psychiatric disorders are related and ii) such a relationship is modulated by the Val158Met polymorphism in the COMT gene. METHOD: Cannabis use profiles and COMT Val158Met genotypes were obtained from 80 inpatients with schizophrenia-spectrum disorders and 77 inpatients with other non-psychotic disorders. RESULTS: First, age at first cannabis use correlates with age at onset in both schizophrenia-spectrum and other psychiatric disorder groups: those who started using cannabis earlier had an earlier age at onset of psychiatric disorders. Second, the distribution of the Val158Met genotypes was not different either between diagnosis groups or between cannabis users and non-users. Third, an interaction between Val158Met genotypes and cannabis use was observed specifically on age at emergence of psychotic disorders, with Val/Val genotype carriers showing an earlier age at onset than Met carriers. CONCLUSION: Our results suggest the importance of brain maturation timing in which exposure to cannabis occurs. The COMT Val158Met genotype seems to modulate the association between cannabis and age at onset of psychotic disorders. These results are consistent with previous studies.

Temporal changes in renal endoglin and TGF-alfa1 expression following ureteral obstruction in rats

Chronic renal disease is characterized by the accumulation of extracellular matrixproteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis hasbeen reported to play an important role in the progression of chronic renal diseases.Transforming growth factor-beta1 (TGF-alpha1) is a profibrotic cytokine playing amajor contribution to fibrotic kidney disease. Endoglin is a membrane glycoproteinof the TGF-alpha1 receptor system. The aim of this work was to determine the timecourseexpression of renal type I and IV collagens, endoglin and TGF-alpha1 in a ratmodel of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateralureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitialfibrosis was detected by Masson’s trichromic and Sirius red staining, accompaniedby an increase in type I collagen expression as shown by immunohistochemicalanalysis. Northern blot studies revealed a progressive increase in collagen alpha2(I),TGF-alpha1 and endoglin mRNA expression in L kidneys when compared with the correspondingnon-ligated (NL) kidneys from the animals subjected to left UUO. Seventeendays after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV),TGF-alpha1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantlyhigher levels of the protein endoglin were found in L kidneys than in NLkidneys 10 and 17 days following obstruction. A marked increase expression forendoglin and TGF-alpha1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulationof endoglin coincident to that of its ligand TGF-alpha1 in the kidneys of rats with progressivetubulointerstitial fibrosis induced by UUO (AU)

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Temporal changes in renal endoglin and TGF-beta1 expression following ureteral obstruction in rats.

Chronic renal disease is characterized by the accumulation of extracellular matrix proteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis has been reported to play an important role in the progression of chronic renal diseases. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine playing a major contribution to fibrotic kidney disease. Endoglin is a membrane glycoprotein of the TGF-beta1 receptor system. The aim of this work was to determine the time-course expression of renal type I and IV collagens, endoglin and TGF-beta1 in a rat model of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateral ureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitial fibrosis was detected by Masson's trichromic and Sirius red staining, accompanied by an increase in type I collagen expression as shown by immunohistochemical analysis. Northern blot studies revealed a progressive increase in collagen alpha2(I), TGF-beta1 and endoglin mRNA expression in L kidneys when compared with the corresponding non-ligated (NL) kidneys from the animals subjected to left UUO. Seventeen days after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV), TGF-beta1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantly higher levels of the protein endoglin were found in L kidneys than in NL kidneys 10 and 17 days following obstruction. A marked increase expression for endoglin and TGF-beta1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulation of endoglin coincident to that of its ligand TGF-beta1 in the kidneys of rats with progressive tubulointerstitial fibrosis induced by UUO.

Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts.

OBJECTIVE: As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGF beta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts. METHODS: We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGF beta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects. RESULTS: Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGF beta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGF beta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGF beta-mediated induction of connective tissue growth factor promoter activity. CONCLUSION: SSc is characterized by overproduction of matrix; that is, genes that are targets of TGF beta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGF beta.

Transforming growth factor-beta1 induces collagen synthesis and accumulation via p38 mitogen-activated protein kinase (MAPK) pathway in cultured L(6)E(9) myoblasts.

Transforming growth factor-beta (TGF-beta) plays a pivotal role in the extracellular matrix accumulation observed in chronic progressive tissue fibrosis, but the intracellular signaling mechanism by which TGF-beta stimulates this process remains poorly understood. We examined whether mitogen-activated protein kinase (MAPK) routes were involved in TGF-beta1-induced collagen expression in L(6)E(9) myoblasts. TGF-beta1 induced p38 and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation whereas no effect on Jun N-terminal kinase phosphorylation was observed. Biochemical blockade of p38 but not of the ERK MAPK pathway abolished TGF-beta1-induced alpha(2)(I) collagen mRNA expression and accumulation. These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis.

Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells.

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-alpha- and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor-mediated endocytic activity; nuclear factor-kappaB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-alpha. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.

Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression.

Signaling by transforming growth factor (TGF)-beta family members is mediated by Smad proteins that regulate gene transcription through functional cooperativity and association with other DNA-binding proteins. The hypoxia-inducible factor (HIF)-1 is a transcriptional complex that plays a key role in oxygen-regulated gene expression. We demonstrate that hypoxia and TGF-beta cooperate in the induction of the promoter activity of vascular endothelial growth factor (VEGF), which is a major stimulus in the promotion of angiogenesis. This cooperation has been mapped on the human VEGF promoter within a region at -1006 to -954 that contains functional DNA-binding sequences for HIF-1 and Smads. Optimal HIF-1alpha-dependent induction of the VEGF promoter was obtained in the presence of Smad3, suggesting an interaction between these proteins. Consistent with this, co-immunoprecipitation experiments revealed that HIF-1alpha physically associates with Smad3. These results demonstrate that both TGF-beta and hypoxia signaling pathways can synergize in the regulation of VEGF gene expression at the transcriptional level.

Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-beta stimulation.

Endoglin, a component of the transforming growth factor-beta (TGF-beta) receptor complex expressed on endothelial cells, is involved in cardiovascular morphogenesis and vascular remodeling, as exemplified by the fact that the endoglin gene is the target for the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia type 1. Since haploinsufficiency is the underlying mechanism for hereditary hemorrhagic telangiectasia type 1, understanding the regulation of endoglin gene expression appears to be a crucial step to correct the disease. In this study we have identified an Sp1 site at -37 as a critical element for the basal transcription of the endoglin TATA-less promoter. Since endoglin promoter activity is stimulated by TGF-beta and this stimulation is located at the Sp1-containing proximal region, we have investigated the possible involvement of Sp1 in the TGF-beta-mediated induction. Mutation of the Sp1-binding sequence, or addition of the Sp1 inhibitor WP631, abolished both the basal transcription activity and the TGF-beta responsiveness of the endoglin promoter. Binding of Sp1 and Smad3 to the proximal promoter region -50/-29 was evidenced by electrophoretic mobility shift assays and DNA affinity precipitation studies. Furthermore, synergistic cooperation on the promoter activity between Sp1 and TGF-beta or Smad3 could be demonstrated by co-transfection experiments of reporter promoter constructs. The molecular mechanism underlying this cooperation appears to involve a direct physical interaction between Sp1 and Smad3/Smad4.

Vascular gene transfer driven by endoglin and ICAM-2 endothelial-specific promoters.

The involvement of the vascular endothelium in a large number of diseases supports the importance of vascular-specific gene delivery for their treatment. The hereditary hemorrhagic telangiectasia type 1 is an example of a vascular inherited disease (OMIM 187300). This is an autosomal dominant vascular disorder originated by mutations in the endoglin gene and associated with frequent epistaxis, telangiectases, gastrointestinal bleedings, and arteriovenous malformations in brain, lung and liver. Here, we address for the first time the possibility of using in vivo gene transfer to target endoglin expression to the vasculature. The promoter of the endothelial gene, ICAM-2, was used to generate transgenic animals which demonstrated endothelial expression of endoglin. Next, the promoters of the human endothelial genes, endoglin and ICAM-2, were inserted upstream of the human endoglin cDNA, and the resulting constructs were systemically or locally delivered, demonstrating endoglin expression in the vessel walls of liver, lung and skin. These gene transfer experiments represent an initial step in the treatment of the hereditary hemorrhagic telangiectasia type 1 by gene therapy, and suggest that endoglin and ICAM-2 promoters can be used to deliver other genes to the endothelium specifically.

Up-regulation of endoglin, a TGF-beta-binding protein, in rats with experimental renal fibrosis induced by renal mass reduction.

BACKGROUND: The central process in chronic renal failure is the progressive accumulation of extracellular matrix in the glomeruli and in the tubulo-interstitial space, resulting in renal fibrosis. Transforming growth factor-beta1 (TGF-beta1) up-regulation plays a major role in the genesis of renal fibrosis. Endoglin is a membrane glycoprotein that binds TGF-beta1 and TGF-beta3 with high affinity. An increased level of endoglin immunostaining has been demonstrated previously in biopsies from patients with chronic progressive renal disease. We have assessed the expression of endoglin in the rat 5/6th renal mass reduction (RMR) model. METHODS: One, 3 and 5 months after RMR, mean arterial pressure and renal function were measured, animals were sacrificed, renal fibrosis was evaluated quantitatively and the expression of endoglin was assessed by western blot, northern blot and immunohistochemistry. RESULTS: RMR induced a progressive increase in mean arterial pressure and urinary protein excretion. Renal corpuscular area, and mesangial and interstitial fibrosis increased with time after RMR. Immunohistochemical staining for endoglin demonstrated its expression mainly on the endothelial surface of major vessels. In kidneys 1 and 3 months after RMR, the expression of endoglin in renal corpuscles was limited to Bowman's parietal epithelium. In rats 5 months after RMR, the immunoexpression in glomerular endothelium was more marked. Northern blot analysis revealed that rats with RMR showed an increase in the expression of mRNA for endoglin, only at 5 months after RMR. Western blot analysis gave a different time course: a marked increase in the first month, a decrease in the 3rd month and a further increase in the 5th month after RMR. CONCLUSIONS: The present study demonstrates increased endoglin expression in rats with severe hypertension and renal damage. This increased endoglin expression coincides with the period of higher renal damage and renal dysfunction.

Endoglin expression in human and rat mesangial cells and its upregulation by TGF-beta1.

Endoglin is a component of the TGF-beta receptor complex present in the kidney at the human glomerular mesangium. Since the cellular origin of the glomerular endoglin is unknown, in the present study we investigated the expression of endoglin in mesangial cells in culture, as well as their response to TGF-beta1. Western and Northern blot analysis identified the expression of endoglin protein and mRNA transcript in both human and rat mesangial cells. Flow cytometry and immunocytochemistry analyses revealed that endoglin is present on the cell membrane. Exogenous TGF-beta1 stimulated not only the expression of collagen alpha1 (I) I and TGF-beta1, but also that of endoglin. These data provide the first evidence for the expression of endoglin in mesangial cells, as well as its upregulation by TGF-beta1, thus suggesting that endoglin may have a role in modulating the effects of TGF-beta1 on the glomerular mesangium.

Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105.

The progression of breast cancer depends on the establishment of a neovasculature, by a process called angiogenesis. Angiogenesis is an invasive cellular event that requires the co-ordination of numerous molecules including growth factors and their receptors, extracellular proteins, adhesion molecules, and proteolytic enzymes. TGFbeta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growth inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. It seems that TGFbeta exerts pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumourigenesis at an early stage by direct inhibition of angiogenesis and tumour cell growth. However, over-production of TGFbeta by an advanced tumour may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression. The cell membrane antigen CD105 (endoglin) binds TGFbeta1 and TGFbeta3 and is preferentially expressed in angiogenic vascular endothelial cells. The reduction of CD105 levels in HUVEC leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGFbeta1. CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. The administration of an immunotoxin-conjugate, mab to CD105, induces long-term and complete regression of breast cancer growth in SCID mice. Therefore, CD105 is a promising vascular target for antiangiogenic therapy.

Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells.

Dendritic cells (DC) are highly specialized APC that are critical for the initiation of T cell-dependent immune responses. DC exert a sentinel function while immature and, after activation by inflammatory stimuli or infectious agents, mature and migrate into lymphoid organs to prime T cells. We have analyzed integrin expression on monocyte-derived DC (MDDC) and found that expression of CD49d integrins (CD49d/CD29 and CD49d/beta7) was induced/up-regulated during TNF-alpha- or LPS-initiated MDDC maturation, reflecting the induction/up-regulation of CD49d and beta7 mRNA. CD49d mRNA steady-state level increased more than 10 times during maturation, with the highest levels observed 24 h after TNF-alpha treatment. CD49d integrin expression conferred mature MDDC with an elevated capacity to adhere to the CS-1 fragment of fibronectin, and also mediated transendothelial migration of mature MDDC. Up-regulation of CD49d integrin expression closely paralleled that of the mature DC marker CD83. CD49d integrin expression was dependent on cell maturation, as its induction was abrogated by N:-acetylcysteine, which inhibits NF-kappaB activation and the functional and phenotypic maturation of MDDC. Moreover, CD49d integrin up-regulation and MDDC maturation were prevented by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase, but were almost unaffected by the mitogen-activated protein/extracellular signal-related kinase kinase 1/2 inhibitor PD98059. Our results support the existence of a link between functional and phenotypic maturation of MDDC and CD49d integrin expression, thus establishing CD49d as a maturation marker for MDDC. The differential expression of CD49d on immature and mature MDDC might contribute to their distinct motility capabilities and mediate mature DC migration into lymphoid organs.

c-Myc inhibits CD11a and CD11c leukocyte integrin promoters.

The c-Myc transcription factor is an important regulator of cell growth and differentiation, and its gene repression ability seems to play a key role in Myc-mediated cellular transformation. Since Myc overexpression has been associated with reduced expression of beta1 and beta2 integrins, we have investigated the role of c-Myc on CD11a and CD11c transcription. c-Myc inhibited CD11a and CD11c integrin promoter activity in co-transfection experiments, and similar repression was obtained in cells where c-Myc expression (KmycB) or activity (Rat-1 c-MycER) is inducible. The c-Myc repression on the CD11c promoter was independent of the USF-binding site (USF-150), other putative Myc-binding elements, or the integrity of the initiator (Inr)-like sequence present at the major transcriptional start site. Analysis of deletion and mutant promoter constructs revealed that, in the absence of additional upstream cisacting elements, an AP-1-binding site at -60 (AP1-60) is required for c-Myc repressor activity. The c-Myc repressor activity on both integrin promoters was abrogated by deletion of c-Myc residues 106-143, a domain involved in Inr-dependent transcriptional repression. These results demonstrate a direct effect of c-Myc on integrin gene transcription and suggest the existence of a c-Myc-dependent mechanism for coupling leukocyte integrin expression to the cell proliferative state.

Polyomavirus enhancer-binding protein 2/core binding factor/acute myeloid leukemia factors contribute to the cell type-specific activity of the CD11a integrin gene promoter.

The CD11a/CD18 leukocyte integrin (LFA-1; also known as alphaL/beta2) mediates leukocyte transendothelial migration during immune and inflammatory responses and participates in lymphoma metastasis. CD11a/CD18 leukocyte-restricted expression is controlled by the CD11a gene promoter, which confers tissue-specific expression to reporter genes in vitro and in vivo. DNase I protection analysis of the CD11a proximal gene promoter revealed DNA-protein interactions centered at position -110 (CD11a-110). Disruption of CD11a-110 reduced CD11a promoter activity in a cell type-specific manner, as it reduced its activity by 70% in Jurkat lymphoid cells, whereas the effect was considerably lower in K562 and HepG2 cells. Electrophoretic mobility shift assays showed evidence of cell type-specific differences in CD11a-110 binding and indicated its specific recognition by members of the polyomavirus enhancer-binding protein 2/core binding factor (CBF)/acute myeloid leukemia (AML) family of transcription factors. AML1B/CBFbeta transactivated the CD11a promoter, with AML1B/CBFbeta-mediated transactivation being completely dependent on the integrity of the CD11a-110 element. Therefore, CBF/AML factors play a role in the cell type-restricted transcription of the CD11a integrin gene through recognition of CD11a-110. The involvement of CBF/AML factors in CD11a expression raises the possibility that CD11a/CD18 expression might be deregulated in acute myeloid and B-lineage acute lymphoblastic leukemias, thus contributing to their altered adhesion and metastatic potential.

Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.

ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-beta superfamily, is the gene mutated in hereditary hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels. ALK-1 levels were specifically reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two newborns not carrying the missense mutations present in the clinically affected relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function of the mutant allele due to a reduction in either protein level or activity. We also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-beta1 and -beta3 receptor complexes in association with endoglin and TbetaRII, but not in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not detectable in the TGF-beta1 or -beta3 receptor complexes. However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients. Our data suggest a transient association between these two proteins of the TGF-beta superfamily, both required at a critical level to ensure vessel wall integrity.

Diagnóstico prenatal de un teratoma intracardíaco: a propósito de un caso / Prenatal diagnosis of intracardiac teratoma: a case report

Aunque los teratomas intracardíacos son tumores extremadamente raros y diagnosticados sobre todo tras el nacimiento, en nuestros días nuestra capacidad de diagnóstico tiende a aumentar gracias al desarrollo tecnológico, incluso prenatalmente. Presentamos un caso de tumor intracardíaco diagnosticado intraútero en la 34 semana de gestación. El tumor se acompañó de derrame pericárdico y rápido desarrollo de hidrops fetal, lo que obligó a programar el fin de gestación y cirugía fetal posterior. Tras el nacimiento se sigue la evolución pre y post-quirúrgica del recién nacido resultando todo un éxito. El estudio anatomopatológico dio como resultado: teratoma intrapericárdico (AU)

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CD105 antagonizes the inhibitory signaling of transforming growth factor beta1 on human vascular endothelial cells.

CD105 (endoglin), a receptor for transforming growth factor beta (TGFbeta), is highly expressed in tissue-cultured, activated endothelial cells in vitro and in tissues undergoing angiogenesis in vivo. The absence of CD105 in knockout mice leads to their death from defective vascular development, but the role of CD105 in the modulation of angiogenesis has not been elucidated. TGFbeta1 is a well-recognized regulator of angiogenesis. Using an antisense approach, we have shown that inhibition of CD105 protein translation in cultured human endothelial cells enhances the ability of TGFbeta1 to suppress growth and migration in these cells. The ability of endothelial cells to form capillary tubes was evaluated by the use of a 3-dimensional collagen matrix system where TGFbeta1 not only reduced the length of capillary-like structures, but also caused massive mortality in CD105-deficient cells compared to control cultures. These results provide direct evidence that CD105 antagonizes the inhibitory effects of TGFbeta1 on human vascular endothelial cells and that normal cellular levels of CD105 are required for the formation of new blood vessels.