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PubMed2002

Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury.

Endoglin is an endothelial membrane glycoprotein involved in cardiovascular morphogenesis and vascular remodeling. It associates with transforming growth factor-beta (TGF-beta) signaling receptors to bind TGF-beta family members, forming a functional receptor complex. Arterial injury leads to up-regulation of endoglin, but the underlying regulatory events are unknown. The transcription factor KLF6, an immediate-early response gene induced in endothelial cells during vascular injury, transactivates TGF-beta, TGF-beta signaling receptors, and TGF-beta-stimulated genes. KLF6 and, subsequently, endoglin were colocalized to vascular endothelium (ie, expressed in the same cell type) following carotid balloon injury in rats. After endothelial denudation, KLF6 was induced and translocated to the nucleus; this was followed 6 hours later by increased endoglin expression. Transient overexpression of KLF6, but not Egr-1, stimulated endogenous endoglin mRNA and transactivated the endoglin promoter. This transactivation was dependent on a GC-rich tract required for basal activity of the endoglin promoter driven by the related GC box binding protein, Sp1. In cells lacking Sp1 and KLF6, transfected KLF6 and Sp1 cooperatively transactivated the endoglin promoter and those of collagen alpha1(I), urokinase-type plasminogen activator, TGF-beta1, and TGF-beta receptor type 1. Direct physical interaction between Sp1 and KLF6 was documented by coimmunoprecipitation, pull-down experiments, and the GAL4 one-hybrid system, mapping the KLF6 interaction to the C-terminal domain of Sp1. These data provide evidence that injury-induced KLF6 and preexisting Sp1 may cooperate in regulating the expression of endoglin and related members of the TGF-beta signaling complex in vascular repair.

Animals↗
PubMed2004

Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes.

BACKGROUND: Mutations in the endoglin (ENG) or ALK1 genes are responsible for hereditary hemorrhagic telangiectasia types 1 and 2 (HHT1 and HHT2), respectively, a dominant vascular dysplasia caused by haploinsufficiency. No formal mutation studies of patients with HHT have been conducted in Spain. METHODS: ENG and ALK1 mutation analyses were carried out in 13 Spanish HHT patients diagnosed according to the Curacao criteria. Because endoglin is up-regulated at the cell surface during the monocyte-macrophage transition, endoglin concentrations in activated monocytes were determined by immunofluorescence flow cytometry in a systematic analysis. As controls, 40 non-HHT volunteers were studied for up-regulation of endoglin in activated monocytes. RESULTS: The mutation responsible for HHT was identified in eight patients belonging to two unrelated families. One of the families has a nonsense mutation in exon 4 (c.511C>T; R171X) of the ENG gene, and accordingly the disorder was identified as HHT1. The other family has a missense mutation affecting exon 8 (c.1120C>T; R374W) of the ALK1 gene, and hence is a HHT2 family. Interestingly, endoglin up-regulation was deficient in activated monocytes of both HHT1 and HHT2 patients compared with controls. By contrast, endoglin up-regulation was age-independent in control donors across a broad range of ages. The extent of endoglin up-regulation in activated monocytes was most diminished in those patients with the most severe symptoms. CONCLUSIONS: Endoglin up-regulation in activated monocytes is impaired in HHT1 and HHT2 patients and is age-dependent in both HHT types. Endoglin expression may predict the clinical severity of HHT.

Antigens, CD↗
PubMed1999

Expression of normal and truncated forms of human endoglin.

Endoglin is a transmembrane glycoprotein 633 residues in length expressed at the surface of endothelial cells as a disulphide-linked homodimer; the specific cysteine residues involved in endoglin dimerization are unknown. Mutations in the coding region of the endoglin gene are responsible for hereditary haemorrhagic telangiectasia type 1 (HHT1), a dominantly inherited vascular disorder. Many of these mutations, if translated, would lead to truncated forms of the protein. It is therefore of interest to assess the protein expression of different truncated forms of endoglin. Infections in vitro or in vivo with recombinant vaccinia virus, as well as transient transfections with expression vectors, were used to express normal and truncated forms of endoglin. Truncated mutants could be classified into three different groups: (1) those that did not produce stable transcripts; (2) those that produced stable transcripts but did not secrete the protein; and (3) those that secreted a soluble dimeric protein. This is the first time that a recombinant truncated form of endoglin has been found to be expressed in a soluble form. Because a chimaeric construct encoding the N-terminal sequence of platelet/endothelial cell adhesion molecule (PECAM-1) antigen fused to residues Ile281-Ala658 of endoglin also yielded a dimeric surface protein, these results suggest that cysteine residues contained within the fragment Cys330-Cys412 are involved in disulphide bond formation. Infection with vaccinia recombinants encoding an HHT1 mutation did not affect the expression of the normal endoglin, and did not reveal an association of the recombinant soluble form with the transmembrane endoglin, supporting a haploinsufficiency model for HHT1.

Animals↗
PubMed1992

Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells.

Endoglin, a dimeric membrane glycoprotein expressed at high levels on human vascular endothelial cells, shares regions of sequence identity with betaglycan, a major binding protein for transforming growth factor-beta (TGF-beta) that co-exists with TGF-beta receptors I and II in a variety of cell lines but is low or absent in endothelial cells. We have examined whether endoglin also binds TGF-beta and demonstrate here that the major TGF-beta 1-binding protein co-existing with TGF-beta receptors I and II on human umbilical vein endothelial cells is endoglin, as determined by specific immunoprecipitation of endoglin affinity-labeled with 125I-TGF-beta. Furthermore, endoglin ectopically expressed in COS cells binds TGF-beta 1. Competition affinity-labeling experiments showed that endoglin binds TGF-beta 1 (KD approximately 50 pM) and TGF-beta 3 with high affinity but fails to bind TGF-beta 2. This difference in affinity of endoglin for the TGF-beta isoforms is in contrast to beta-glycan which recognizes all three isoforms. TGF-beta however is binding with high affinity to only a small fraction of the available endoglin molecules, suggesting that some rate-limiting event is required to sustain TGF-beta binding to endoglin.

Antigens, CD↗
PubMed1998

Endoglin, a component of the TGF-beta receptor system, is a differentiation marker of human choriocarcinoma cells.

Endoglin is an integral membrane glycoprotein that binds transforming growth factor-beta1 (TGF-beta1) with high affinity and it is strongly expressed on syncytiotrophoblasts throughout pregnancy. Here, we describe the expression of endoglin by the choriocarcinoma cell line JAR as evidenced by flow cytometry, immunoprecipitation, Western blot and reverse transcriptase polymerase chain reaction analyses. Cross-linking experiments of [125I]-labeled TGF-beta1 to JAR cells indicated that endoglin expressed at the surface of these cells binds TGF-beta. Furthermore, staining of human choriocarcinoma tissue sections with a polyclonal antibody to endoglin demonstrated a high expression of endoglin in syncytiotrophoblast-like areas, as opposed to a negative staining of cytotrophoblast-like cells. This pattern of endoglin expression was confirmed by experiments with methotrexate, an inducer of giant, multinucleated, non-proliferative cells, morphologically indistinguishable from the naturally occurring syncytiotrophoblasts. Thus, treatment of the JAR and JEG-3 choriocarcinoma cell lines with methotrexate led to an increase in endoglin expression, as demonstrated by Western and Northern blot analyses. Taken together, our results suggest that endoglin, in addition to being involved in placental development, may also be a cellular differentiation marker.

Antigens, CD↗
PubMed2004

Active immunotherapy of tumors with a recombinant xenogeneic endoglin as a model antigen.

Angiogenesis play a critical role in tumor growth and metastasis. Increasing evidence suggests that endoglin is a powerful marker of angiogenesis in solid malignancies. Thus, breaking of immune tolerance of self-endoglin-associated angiogenesis is an attractive approach to cancer therapy. To test this concept, we recombined the extracellular domains of porcine endoglin, and used it as a xenogeneic vaccine. We found that immunotherapy with porcine endoglin was effective at both protective and therapeutic anti-tumor immunity in several mouse tumor models. Autoantibodies against mouse endoglin were identified by Western blot and ELISA. IgG1 and IgG2b were substantially increased. Anti-endoglin antibody-producing B cells were detectable by ELISPOT assay. There was endothelial deposition of immunoglobulins within tumors. The anti-tumor activity was also induced by the adoptive transfer of the purified immunoglobulins. Angiogenesis was apparently inhibited within the tumor tissues and on the alginate beads. The increased apoptotic cells were found within the tumor tissues from the mice treated with porcine endoglin. The anti-tumor activity and production of autoantibodies against mouse endoglin could be abrogated by depletion of CD4(+) T lymphocytes. Remarkably, no marked toxicity was found in the immunized mice. These observations may provide an alternative rational strategy for active cancer immunotherapy.

Adoptive Transfer↗
PubMed2005

Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex.

Transforming growth factor-beta (TGF-beta) signaling in endothelial cells is able to modulate angiogenesis and vascular remodeling, although the underlying molecular mechanisms remain poorly understood. Endoglin and ALK-1 are components of the TGF-beta receptor complex, predominantly expressed in endothelial cells, and mutations in either endoglin or ALK-1 genes are responsible for the vascular dysplasia known as hereditary hemorrhagic telangiectasia. Here we find that the extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). In addition, endoglin potentiates TGF-beta/ALK1 signaling, with the extracellular domain of endoglin contributing to this functional cooperation between endoglin and ALK-1. By contrast, endoglin appears to interfere with TGF-beta/ALK-5 signaling. These results suggest that the functional association of endoglin with ALK-1 is critical for the endothelial responses to TGF-beta.

Activin Receptors, Type I↗
PubMed2001

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.

Animals↗
PubMed1995

Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease.

The ingress of inflammatory cells into the rheumatoid (RA) synovial tissue (ST) plays a role in the pathogenesis of this disease. Transforming growth factor beta (TGF-beta) may play a role in this process. We have investigated the distribution of endoglin, a newly described receptor for TGF-beta 1 and -beta 3, in RA compared to osteoarthritis (OA) or normal ST. Immunohistochemical analysis was carried out using an anti-TGF-beta 1 monoclonal antibody (mAb) as well as 10 mAbs raised against various epitopes of endoglin. This study was performed on ST from 10 patients with RA, 10 with OA, and 4 normal individuals. TGF-beta 1 expression was significantly up-regulated on RA compared to OA and normal ST lining cells, interstitial macrophages, and endothelial cells (P < 0.05). All anti-endoglin mAbs uniformly reacted with endothelial cells in RA, OA, and normal STs. However, 3 out of 10 anti-endoglin mAbs reacted with significantly more RA versus normal ST lining cells (P < 0.05), as well as RA compared to OA and normal macrophages (P < 0.05). There was a positive correlation between TGF-beta 1 and endoglin reactivity on the synovial lining layer and subsynovial macrophages (P < 0.05). These results indicate that TGF-beta 1 and certain epitopes of endoglin, a TGF-beta 1 and -beta 3 receptor, are up-regulated on myeloid elements in RA compared to normal ST. Endoglin is also present on ST endothelia, and its expression may also be increased on OA compared to normal ST lining cells. These findings implicate endoglin in the pathogenesis of RA.

Antibodies, Monoclonal↗
PubMed2004

Expression of endoglin in choroidal neovascularization.

Endoglin (CD105) is a membrane protein involved in the TGF-beta receptor signalling pathway with predominant expression by proliferating endothelial cells. The aim of this study is to analyze the expression of Endoglin in choroidal neovascularization membranes (CNVM) and to compare it to the overall proliferative status of CNVM. Thirty surgically excised CNVM, secondary to age-related macular degeneration, were investigated using light microscopic immunohistochemistry and confocal immunofluorescence microscopy using verified antibodies directed against the endothelial cell markers Endoglin, von Willebrand factor (vWF) and CD34 and the proliferation marker Ki-67. Donor eyes were used as controls. A selective expression of CD34 and vWF as well as Endoglin was found in endothelial cells. Endoglin expression was elevated in vascular endothelial cells contained within CNVM, but a moderate Endoglin expression could also be visualized in quiescent CD34 and vWF positive ocular vasculature. Ki-67 positive cells were detected in CNVM, but these were rarely endothelial cells. Endoglin expression in endothelial cells of CNVM is increased, but rarely associated with a concomitant expression of the proliferation marker Ki-67. The elevated expression of Endoglin in surgically excised CNVM suggests a persisting post-mitotic activation in an advanced stage of this neovascular tissue.

Antigens, CD↗
PubMed2006

Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia.

Endoglin is a type I membrane protein expressed as a disulphide-linked homodimer on human vascular endothelial cells whose haploinsufficiency is responsible for the dominant vascular dysplasia known as hereditary hemorrhagic telangiectasia (HHT). Structurally, endoglin belongs to the zona pellucida (ZP) family of proteins that share a ZP domain of approximately 260 amino acid residues at their extracellular region. Endoglin is a component of the TGF-beta receptor complex, interacts with the TGF-beta signalling receptors types I and II, and modulates cellular responses to TGF-beta. Here, we have determined for the first time the three-dimensional structure of the approximately 140 kDa extracellular domain of endoglin at 25 A resolution, using single-particle electron microscopy (EM). This reconstruction provides the general architecture of endoglin, which arranges as a dome made of antiparallel oriented monomers enclosing a cavity at one end. A high-resolution structure of endoglin has also been modelled de novo and found to be consistent with the experimental reconstruction. Each subunit comprises three well-defined domains, two of them corresponding to ZP regions, organised into an open U-shaped monomer. This domain arrangement was found to closely resemble the overall structure derived experimentally and the three modelled de novo domains were tentatively assigned to the domains observed in the EM reconstruction. This molecular model was further tested by tagging endoglin's C terminus with an IgG Fc fragment visible after 3D reconstruction of the labelled protein. Combined, these data provide the structural framework to interpret endoglin's functional domains and mutations found in HHT patients.

Amino Acid Sequence↗
PubMed2004

Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer.

Endoglin (CD105) has been shown to be a more useful marker to identify proliferating endothelium involved in tumor angiogenesis than panendothelial markers such as CD31. We investigated endoglin and vascular endothelial growth factor expression as possible prognostic markers in colorectal cancer. Surgical specimens from 150 patients with resected colorectal carcinomas were immunostained for endoglin, CD31 and vascular endothelial growth factor. Colorectal carcinoma cases consisted of 50 cases without lymph node metastases, 50 cases with only lymph node metastases and 50 cases with liver metastases (38 cases also had positive lymph nodes). Positively stained microvessels were counted in densely vascular foci (hot spots) at x 400 fields in each specimen. For vascular endothelial growth factor, intensity of staining was scored on a three-tiered scale. Results were correlated with other prognostic parameters. Endoglin demonstrated significantly more proliferating neoplastic microvessels than CD31 (31+/-10 vs 19+/-8/0.15 mm2 field, P<0.001). Low vascular endothelial growth factor expression within tumor cells was seen in 49 (33%) and high expression in 101 cases (67%). There was a positive correlation of endoglin, CD31 counts and vascular endothelial growth factor overexpression with the presence of angiolymphatic invasion and lymph node metastases (P<0.05). Only endoglin counts correlated significantly with liver metastases and positive vascular pedicle lymph nodes (P<0.05), while vascular endothelial growth factor showed significant correlation with the depth of invasion (P<0.01). Endoglin, by staining higher numbers of the proliferating vessels in colon carcinoma, is a more specific and sensitive marker for tumor angiogenesis than the commonly used panendothelial markers. Endoglin staining also showed prognostic significance with positive correlation with angiolymphatic invasion and metastases to lymph nodes and liver.

Adult↗
PubMed2003

Expression of the TGF-beta coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis.

Endoglin is an integral membrane glycoprotein primarily expressed in the vascular endothelium, but also found on macrophages and stromal cells. It binds several members of the transforming growth factor (TGF)-beta family of growth factors and modulates TGF-beta(1)-dependent cellular responses. However, it lacks cytoplasmic signaling motifs and is considered as an auxiliary receptor for TGF-beta. We show here that endoglin is expressed in mouse and human epidermis and in skin appendages, such as hair follicles and sweat glands, as determined by immunohistochemistry. In normal interfollicular epidermis, endoglin was restricted to basal keratinocytes and absent in differentiating cells of suprabasal layers. Follicular expression of endoglin was high in hair bulb keratinocytes, but decreased in parts distal from the bulb. To address the role of endoglin in skin carcinogenesis in vivo, Endoglin heterozygous mice were subjected to long-term chemical carcinogenesis treatment. Reduction in endoglin had a dual effect during multistage carcinogenesis, by inhibiting the early appearance of benign papillomas, but increasing malignant progression to highly undifferentiated carcinomas. Our results are strikingly similar to those previously reported for transgenic mice overexpressing TGF-beta(1) in the epidermis. These data suggest that endoglin might attenuate TGF-beta(1) signaling in normal epidermis and interfere with progression of skin carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-beta signalling receptors.

Transforming growth factor-beta (TGF-beta) plays an important role in angiogenesis and vascular function. Endoglin, a transmembrane TGF-beta binding protein, is highly expressed on vascular endothelial cells and is the target gene for the hereditary haemorrhagic telangiectasia type I (HHT1), a dominantly inherited vascular disorder. The specific function of endoglin responsible for HHT1 is believed to involve alterations in TGF-beta responses. The initial interactions on the cell surface between endoglin and TGF-beta receptors may be an important mechanism by which endoglin modulates TGF-beta signalling, and thereby responses. Here it is shown that on human microvascular endothelial cells, endoglin is co-expressed and is associated with betaglycan, a TGF-beta accessory receptor with which endoglin shares limited amino acid homology. This complex formation may occur in either a ligand-dependent or a ligand-independent manner. In addition, the occurrence of three higher order complexes containing endoglin, type II and/or type I TGF-beta receptors, on these cells is demonstrated. Our findings suggest that endoglin may modify TGF-beta signalling by interacting with both betaglycan and the TGF-beta signalling receptors at physiological receptor concentrations and ratios.

Affinity Labels↗
PubMed2004

Identification of endoglin in rat hepatic stellate cells: new insights into transforming growth factor beta receptor signaling.

Transforming growth factor beta (TGF-beta) signaling is mediated by the cell surface TGF-beta type I (ALK5), type II, and the accessory type III receptors endoglin and betaglycan. Hepatic stellate cells (HSC), the most profibrogenic cell type in the liver, express ALK5, TbetaRII, and betaglycan. To monitor the expression of betaglycan in HSC, we used the commercially available antibody sc-6199 in Western blot analysis. This antibody, raised against a peptide mapping at the carboxyl terminus of the human betaglycan, is claimed to be specific for betaglycan, although it is known that the C-terminal domain is highly conserved in type III receptors. Proteins recognized in HSC by sc-6199 did not match the characteristic migration pattern of betaglycan. Moreover, the determined molecular weight (M(r) 160) and the observed reductant sensitivity after treatment with dithiothreitol resemble those of a closely related type III receptor, endoglin (CD105). Endoglin, a disulfide-linked homodimer, is an accessory component of the TGF-beta receptor complex and mainly expressed on endothelial cells. The presence of endoglin in HSC of rat liver was confirmed by molecular cloning of the endoglin cDNA and immunocytochemistry. The reactivity of sc-6199 with both auxiliary TGF-beta receptors (betaglycan and endoglin) from rats was demonstrated by Western blot and immunocytochemical analysis of cells heterologously expressing these proteins. Furthermore, Northern and Western blotting revealed that both betaglycan and endoglin genes are differentially regulated in HSC and in transdifferentiated myofibroblasts (MFB). By surface labeling and immunoprecipitation experiments, we show that endoglin is found in significant amounts exposed at the plasma membrane of HSC and MFB, which is a pivotal prerequisite for binding of and signaling in response to TGF-beta. In conclusion, we hypothesize that TGF-beta signals in HSC and MFB are tuned by two different interconnected signaling pathways, as it was previously demonstrated for endothelial cells.

Amino Acid Sequence↗
PubMed1992

Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells, and syncytiotrophoblasts.

Endoglin is a glycoprotein expressed predominantly on human endothelial cells. It was first identified with mAb 44G4, produced against the pre-B acute lymphoblastic HOON cell line. We now report that four mAbs independently produced against human umbilical vein endothelial cells (HUVECs), chronic myelogenous leukemia in blast crisis, or U-937 pro-monocytic cells stimulated with phorbol myristate acetate also react with endoglin. High levels of reactivity of all mAbs were observed with HUVEC, while intermediate levels were seen with HOON and U-937 cells. By sequential immunoprecipitation from HUVEC and U-937 cell extracts, it was established that RMAC8, HEC-19, 8E11, and 1G2 mAbs react with the same protein as 44G4. Three distinct epitopes recognized by 44G4, RMAC8, and 1G2 mAbs were identified by competitive radioimmunoassay and flow cytometry. The HEC-19 epitope is spatially related to the 44G4 epitope, whereas the 8E11 epitope is most closely related to the 1G2 epitope. Western blot analysis showed that all antibodies react with the endoglin dimer (Mr = 170,000) purified from placenta. Immunostaining of sections of full-term placenta revealed reactivity not only with fetal vessels but also with the syncytiotrophoblast, the fetal cell layer which interfaces with maternal blood. When HUVEC monolayers were treated with the different mAbs to endoglin, prior to incubation with U-937 cells, a 5- to 10-fold stimulation of adhesion was observed. A fibronectin hexapeptide containing RGD, but not the corresponding RGE peptide, was capable of inhibiting the increased adhesion, when tested with mAb 44G4 and RMAC8. However, the same peptides had no effect on the binding of any of the five anti-endoglin mAbs to cells. Since 44G4 and RMAC8 recognize two distinct epitopes of endoglin, and since all five mAbs stimulated adhesion, the results suggest that a signal has been triggered through endoglin on HUVECs. Endoglin might be implicated either directly, by binding to a specific integrin-like ligand, or indirectly, by regulating the level of adhesion between certain integrins and their receptors.

Amino Acid Sequence↗
PubMed2003

Endoglin (CD105) expression in endometrial carcinoma.

Tumor angiogenesis plays an important role in tumor growth and metastasis. We evaluated endoglin (CD105) as an endothelial marker of angiogenesis in endometrial carcinoma (EC) and its prognostic significance. Fifty-five cases of EC, 10 cases of complex endometrial hyperplasia with atypia (CHA), and 10 cases of simple hyperplasia (SH) were immunohistochemically stained for endoglin, CD31, and vascular endothelial growth factor (VEGF). Positively stained microvessels (MV) were counted in densely vascular foci (hot spots) in a 400x field in each specimen. For VEGF, intensity of staining was scored on three-tiered scale. Results were correlated with other prognostic parameters using appropriate statistics. Endoglin staining demonstrated significantly more MV than did CD31 (mean 30.8 +/- 10.95 vs. 13.38 +/- 7.53, p < 0.001). There was a positive correlation of both endoglin and CD31 MV counts with tumor differentiation (p < 0.05) and the depth of invasion (p < 0.01). However, only endoglin counts correlated significantly with the presence of angiolymphatic invasion (p < 0.01), lymph nodes metastases (p < 0.01), and tumor stage (p < 0.001). VEGF expression in EC had a significant correlation with angiolymphatic invasion (p < 0.01) and lymph node status (p < 0.05) but not with other prognostic parameters. Endoglin and VEGF showed significant differences between CHA and SH (p < 0.001). Our study showed that endoglin, by staining the proliferating MV in EC, is a more specific and sensitive marker for tumor angiogenesis than is the commonly used pan-endothelial marker, CD31. Endoglin staining also had prognostic significance, with positive correlation with angiolymphatic invasion, lymph node metastases, and tumor stage.

Adult↗
PubMed2006

Endoglin regulates cyclooxygenase-2 expression and activity.

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 E(2) 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 N(omega)-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng(+/+) mice. N(omega)-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-beta1 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(+/-) mice.

Animals↗