Zvýšená angiogeneze byla v poslední době prokázána u akutních a chronických leukemií, lymfomů i myeloproliferací. Endoglin (CD105), člen receptorového komplexu pro transformující růstový faktor beta (TGF-beta), ovlivňuje buněčnou odpověď na TGF-beta a je absolutně nezbytný pro angiogenní pochody. Solubilní endoglin (sCD105) je zvýšený v krvi u nemocných s některými solidními nádory. V naší pilotní studii jsme měřili sCD105 ELISA metodou v plazmě periferní krve u 75 nemocných s lymfoidními malignitami a 13 zdravých dobrovolníků. Zjistili jsme signifikantně zvýšenou koncentraci sCD105 u nemocných s chronickou B-lymfocytární leukemií (n = 42) v porovnání s kontrolní skupinou (p = 0,0296). Překvapivým zjištěním bylo signifikantní snížení sCD105 u nemocných s mnohočetným myelomem (n = 13, p = 0,0023). Koncentrace solubilního endoglinu se nelišily od kontrol u difuzního velkobuněčného (n = 12) ani folikulárního (n = 8) lymfomu. Naše data ukazují, že sCD105 jakožto nový ukazatel angiogeneze u lymfoidních malignit může společně s dalšími angiogenními cytokiny (jako jsou např. VEGF - vascular endothelial growth factor nebo bFGF – basic fibroblast growth factor) napomoci komplexnějšímu zhodnocení angiogeneze s cílem přispět k prognostické stratifikaci u těchto onemocnění.
Increased angiogenesis has been recently reported in acute and chronic leukemias, lymphomas, and myeloproliferative disorders. Endoglin (CD105), a member of transforming growth factor beta (TGF-beta) receptor family, modulates cellular responses to TGF-beta and is absolutely essential for angiogenesis. Its soluble form (sCD105) is increased in patients with various solid tumors. In our pilot study, we measured peripheral blood plasma concentrations of sCD105 using comercially available enzyme-linked immunosorbent assay in 75 patients with lymphoid malignancies and 13 healthy donors. We found a statistically significant increase in sCD105 concentrations in patients with B-cell chronic lymphocytic leukemia (n = 42) compared to the control group (p = 0.0296). Suprisingly, patients with multiple myeloma (n = 13) had significantly lower concentrations of sCD105 in comparison to controls (p = 0.0023). We didn’t find significant differences between sCD105 concentrations in patients with follicular lymphoma (n = 8) or diffuse large B-cell lymphoma (n = 12) and the control group. We conclude that plasma sCD105 is a new angiogenesis marker in lymphoid malignancies and together with other cytokines (such as VEGF - vascular endothelial growth factor and bFGF – basic fibroblast growth factor) might be useful as a part of complex angiogenesis assessment aimed to improve prognostic stratification of these disorders.
- MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell MeSH
- Enzyme-Linked Immunosorbent Assay utilization MeSH
- Research Support as Topic MeSH
- Hemic and Lymphatic Diseases diagnosis MeSH
- Angiogenesis Inducing Agents MeSH
- Humans MeSH
- Multiple Myeloma MeSH
- Prognosis MeSH
- Case-Control Studies MeSH
- Transforming Growth Factor beta MeSH
- Check Tag
- Humans MeSH
BACKGROUND AND AIMS: Increased plasma levels of soluble endoglin (sEng) were detected in patients with endothelial dysfunction-related disorders and hypercholesterolemia. In this study, we hypothesized that high levels of sEng accompanied by mild hypercholesterolemia could aggravate endothelial and vessel wall dysfunction and affect endoglin/eNOS signaling in mouse aorta. METHODS: Three-month-old female transgenic mice on CBAxC57BL/6J background, with high levels of sEng (Sol-Eng+high HFD), and their littermates with low levels of sEng (Sol-Eng+low HFD), were fed a high fat diet for six months. Plasma samples were used for biochemical, ELISA and Luminex analyses of total cholesterol, sEng and inflammatory markers. Functional parameters of aorta were assessed with wire myograph 620M. Western blot analyses of membrane endoglin/eNOS signaling and endothelial dysfunction/inflammation markers in aorta were performed. RESULTS: Functional analysis of aorta showed impaired KCl induced vasoconstriction, endothelial-dependent relaxation after the administration of acetylcholine as well as endothelial-independent relaxation induced by sodium nitroprusside in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. Ach-induced vasodilation after administration of l-NAME was significantly higher in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. The expression of endoglin, p-eNOS/eNOS, pSmad2/3/Smad2/3 signaling pathway was significantly lower in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. CONCLUSIONS: The results indicate that long-term hypercholesterolemia combined with high levels of sEng leads to the aggravation of endothelial and vessel wall dysfunction in aorta, with possible alterations of the membrane endoglin/eNOS signaling, suggesting that high levels of soluble endoglin might be considered as a risk factor of cardiovascular diseases.
- MeSH
- Aorta metabolism pathology physiopathology MeSH
- Atherosclerosis genetics metabolism pathology physiopathology MeSH
- Endothelium, Vascular metabolism pathology physiopathology MeSH
- Diet, High-Fat MeSH
- Endoglin genetics metabolism MeSH
- Phosphorylation MeSH
- Hypercholesterolemia complications etiology MeSH
- Humans MeSH
- Inflammation Mediators metabolism MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice, Inbred CBA MeSH
- Mice, Transgenic MeSH
- Aortic Diseases genetics metabolism pathology physiopathology MeSH
- Smad2 Protein metabolism MeSH
- Smad3 Protein metabolism MeSH
- Signal Transduction MeSH
- Nitric Oxide Synthase Type III metabolism MeSH
- Up-Regulation MeSH
- Vasodilation MeSH
- Vasoconstriction MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Liver sinusoidal endothelial cells (LSECs) play a crucial role in regulating the hepatic function. Endoglin (ENG), a transmembrane glycoprotein, was shown to be related to the development of endothelial dysfunction. In this study, we hypothesized the relationship between changes in ENG expression and markers of liver sinusoidal endothelial dysfunction (LSED) during liver impairment. Male C57BL/6J mice aged 9-12 weeks were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet (intrahepatic cholestasis) or choline-deficient l-amino acid defined high-fat diet (CDAA-HFD) (non-alcoholic steatohepatitis (NASH)). Significant increases in liver enzymes, fibrosis, and inflammation biomarkers were observed in both cholestasis and NASH. Decreased p-eNOS/eNOS and VE-cadherin protein expression and a significant increase in VCAM-1 and ICAM-1 expression were detected, indicating LSED in both mouse models of liver damage. A significant reduction of ENG in the DDC-fed mice, while a significant increase of ENG in the CDAA-HFD group was observed. Both DDC and CDAA-HFD-fed mice showed a significant increase in MMP-14 protein expression, which is related to significantly increased levels of soluble endoglin (sENG) in the plasma. In conclusion, we demonstrated that intrahepatic cholestasis and NASH result in an altered ENG expression, predominantly in LSECs, suggesting a critical role of ENG expression for the proper function of liver sinusoids. Both pathologies resulted in elevated sENG levels, cleaved by MMP-14 expressed predominantly from LSECs, indicating sENG as a liver injury biomarker.
- MeSH
- Acetamides * MeSH
- Diet, High-Fat adverse effects MeSH
- Endoglin metabolism MeSH
- Endothelial Cells metabolism MeSH
- Cholestasis, Intrahepatic * MeSH
- Matrix Metalloproteinase 14 MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Non-alcoholic Fatty Liver Disease * pathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
AIMS: Endoglin is a transmembrane glycoprotein, that plays an important role in regulating endothelium. Proteolytic cleavage of membrane endoglin releases soluble endoglin (sEng), whose increased plasma levels have been detected in diseases related to the cardiovascular system. It was proposed that sEng might damage vascular endothelium, but detailed information about the potential mechanisms involved is not available. Thus, we hypothesized that sEng contributes to endothelial dysfunction, leading to a pro-inflammatory phenotype by a possible modulation of the TGF-β and/or inflammatory pathways. MAIN METHODS: Human umbilical vein endothelial cells (HUVECs) and Human embryonic kidney cell line (HEK293T) were treated with different sEng concentration and time in order to reveal possible effect on biomarkers of inflammation and TGF-β signaling. IL6 and NFκB reporter luciferase assays, quantitative real-time PCR analysis, Western blot analysis and immunofluorescence flow cytometry were used. KEY FINDINGS: sEng treatment results in activation of NF-κB/IL-6 expression, increased expression of membrane endoglin and reduced expression of Id-1. On the other hand, no significant effects on other markers of endothelial dysfunction and inflammation, including eNOS, peNOS(S1177), VCAM-1, COX-1, COX-2 and ICAM-1 were detected. SIGNIFICANCE: As a conclusion, sEng treatment resulted in an activation of NF-κB, IL-6, suggesting activation of pro-inflammatory phenotype in endothelial cells. The precise mechanism of this activation and its consequence remains to be elucidated. A combined treatment of sEng with other cardiovascular risk factors will be necessary in order to reveal whether sEng is not only a biomarker of cardiovascular diseases, but also a protagonist of endothelial dysfunction.
- MeSH
- Endoglin biosynthesis MeSH
- Human Umbilical Vein Endothelial Cells metabolism MeSH
- HEK293 Cells MeSH
- Inhibitor of Differentiation Protein 1 biosynthesis MeSH
- Interleukin-6 biosynthesis MeSH
- Humans MeSH
- NF-kappa B biosynthesis MeSH
- Gene Expression Regulation * MeSH
- Solubility MeSH
- Signal Transduction * MeSH
- Inflammation chemically induced metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Age-related macular degeneration (AMD) is a progressive chronic disease causing visual impairment or central vision loss in the elderly. We hypothesized that successful rheopheresis would be associated with positive changes in soluble endoglin (sENG), PSCK9, alpha-2-macroglobulin (A2M), and hs-CRP levels. 31 elderly patients with the dry form of AMD, treated with rheopheresis with a follow-up period of at least 5 years and an average age of 68 ± 4 years, were evaluated. Each treated patient received a series of 8 procedures in 10 weeks and, after the 2-year period, another 2 procedures within 1 week. Then, the patients were followed up every 6 months and divided into the successfully treated and therapeutic failure group according to best-corrected visual acuity (BCVA), size of the drusen area, and the drusenoid pigment epithelium detachment (DPED). Based on the ophthalmological assessment, rheopheresis treatment was successful in 73% of AMD patients. The therapy was associated with a significant decrease in total cholesterol, LDL-C, HDL-C, apoprotein B, lipoprotein (a) levels, and rheologically important parameters, irrespective of the therapy's success or failure. The success of rheopheresis therapy was exclusively related to a significant decrease in sENG and A2M levels. Over the long term, rheopheresis prevented the decline of BCVA, reduced the DPED and area of macular drusen, and improved the preservation of an intact photoreceptor ellipsoid zone in most patients. Moreover, we showed for the first time that sENG and A2M could be potentially sensitive biomarkers of successful rheopheresis procedure, irrespective of lipid parameters changes.
- MeSH
- Biomarkers * blood MeSH
- Endoglin * blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Macular Degeneration * therapy blood MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Visual Acuity MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
A soluble form of endoglin (sEng) is known to be an extracellular domain of the full-length membrane endoglin, which is elevated during various pathological conditions related to vascular endothelium. In the current review, we tried to summarize a possible role of soluble endoglin in cardiovascular pathologies, focusing on its relation to endothelial dysfunction and cholesterol levels. We discussed sEng as a proposed biomarker of cardiovascular disease progression, cardiovascular disease treatment and endothelial dysfunction. We also addressed a potential interaction of sEng with TGF-β/eNOS or BMP-9 signaling. We suggest soluble endoglin levels to be monitored, because they reflect the progression/treatment efficacy of cardiovascular diseases related to endothelial dysfunction and hypercholesterolemia. A possible role of soluble endoglin as an inducer of endothelial dysfunction however remains to be elucidated.
- MeSH
- Biomarkers blood MeSH
- Antigens, CD blood MeSH
- Endothelium, Vascular metabolism physiopathology MeSH
- Hypercholesterolemia blood complications physiopathology therapy MeSH
- Cardiovascular Diseases blood etiology physiopathology therapy MeSH
- Humans MeSH
- Prognosis MeSH
- Receptors, Cell Surface blood MeSH
- Growth Differentiation Factors metabolism MeSH
- Signal Transduction MeSH
- Nitric Oxide Synthase Type III metabolism MeSH
- Transforming Growth Factor beta metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- MeSH
- Vascular Cell Adhesion Molecule-1 * pharmacology metabolism drug effects MeSH
- Endothelium, Vascular * physiology physiopathology MeSH
- Endoglin MeSH
- Hypercholesterolemia * MeSH
- Hypertension * chemically induced MeSH
- Cardiovascular System * MeSH
- Animals, Laboratory * MeSH
- Humans MeSH
- Membrane Glycoproteins * MeSH
- Mice * MeSH
- Drug Evaluation, Preclinical * methods statistics & numerical data MeSH
- Risk Factors * MeSH
- Nitric Oxide Synthase Type III * MeSH
- Inflammation * MeSH
- Check Tag
- Humans MeSH
- Mice * MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Introduction: Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. sEng is now considered an important biomarker of cardiometabolic disorders. We aimed to evaluate the potentially harmful effects of high sEng levels in combination with other risk factors of cardiometabolic disorders. Results: We demonstrated the harmful effects of sEng with respect to the development of endothelial dysfunction and liver disorders. Long-term hypercholesterolemia combined with high levels of sEng resulted in the aggravation of endothelial and vessel wall dysfunction in the aorta, with possible alterations of the membrane endoglin/eNOS. In addition, long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. sEng also activates the expression of BM4, resulting in the development of arterial hypertension. Moreover, high levels of human sEng result in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirects the metabolism of triglycerides (TAG) to its accumulation in the liver via reduced TAG elimination by -oxidation combined with reduced hepatic efflux. Finally, sEng was shown to be reduced after Lipoprotein apheresis (after each procedure and in long term perspective) in patients with Familial hypercholesterolemia. Conclusion: In conclusion, we propose that sEng can be considered a risk factor for the development of vascular dysfunction and liver alteration, suggesting it might be the potential therapeutical target for pharmacological intervention in these cardiometabolic disorders.
- Publication type
- Meeting Abstract MeSH
Soluble endoglin (sEng) released into the circulation was suggested to be related to cardiovascular based pathologies. It was demonstrated that a combination of high sEng levels and long-term exposure (six months) to high fat diet (HFD) resulted in aggravation of endothelial dysfunction in the aorta. Thus, in this study, we hypothesized that a similar experimental design would affect the heart morphology, TGFβ signaling, inflammation, fibrosis, oxidative stress and eNOS signaling in myocardium in transgenic mice overexpressing human sEng. Three-month-old female transgenic mice overexpressing human sEng in plasma (Sol-Eng+ high) and their age-matched littermates with low levels of human sEng (Sol-Eng+ low) were fed a high-fat diet containing 1.25% of cholesterol and 40% of fat for six months. A blood analysis was performed, and the heart samples were analyzed by qRT-PCR and Western blot. The results of this study showed no effects of sEng and HFD on myocardial morphology/hypertrophy/fibrosis. However, the expression of pSmad2/3 and p-eNOS was reduced in Sol-Eng+ high mice. On the other hand, sEng and HFD did not significantly affect the expression of selected members of TGFβ signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1), inflammation (VCAM-1, ICAM-1), oxidative stress (NQO1, HO-1) and heart remodeling (PDGFβ, COL1A1, β-MHC). In conclusion, the results of this study confirmed that sEng, even combined with a high-fat diet inducing hypercholesterolemia administered for six months, does not affect the structure of the heart with respect to hypertrophy, fibrosis, inflammation and oxidative stress. Interestingly, pSmad2/3/p-eNOS signaling was reduced in both the heart in this study and the aorta in the previous study, suggesting a possible alteration of NO metabolism caused by six months exposure to high sEng levels and HFD. Thus, we might conclude that sEng combined with a high-fat diet might be related to the alteration of NO production due to altered pSmad2/3/p-eNOS signaling in the heart and aorta.
- MeSH
- Aorta metabolism pathology MeSH
- Diet, High-Fat adverse effects MeSH
- Endoglin * blood metabolism MeSH
- Fibrosis MeSH
- Hypercholesterolemia metabolism MeSH
- Hypertrophy MeSH
- Myocardium metabolism pathology MeSH
- Mice, Inbred C57BL MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Nitric Oxide metabolism MeSH
- Oxidative Stress MeSH
- Inflammation MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Membrane endoglin (Eng, CD105) is a transmembrane glycoprotein essential for the proper function of vascular endothelium. It might be cleaved by matrix metalloproteinases to form soluble endoglin (sEng), which is released into the circulation. Metabolic syndrome comprises conditions/symptoms that usually coincide (endothelial dysfunction, arterial hypertension, hyperglycemia, obesity-related insulin resistance, and hypercholesterolemia), and are considered risk factors for cardiometabolic disorders such as atherosclerosis, type II diabetes mellitus, and liver disorders. The purpose of this review is to highlight current knowledge about the role of Eng and sEng in the disorders mentioned above, in vivo and in vitro extent, where we can find a wide range of contradictory results. We propose that reduced Eng expression is a hallmark of endothelial dysfunction development in chronic pathologies related to metabolic syndrome. Eng expression is also essential for leukocyte transmigration and acute inflammation, suggesting that Eng is crucial for the regulation of endothelial function during the acute phase of vascular defense reaction to harmful conditions. sEng was shown to be a circulating biomarker of preeclampsia, and we propose that it might be a biomarker of metabolic syndrome-related symptoms and pathologies, including hypercholesterolemia, hyperglycemia, arterial hypertension, and diabetes mellitus as well, despite the fact that some contradictory findings have been reported. Besides, sEng can participate in the development of endothelial dysfunction and promote the development of arterial hypertension, suggesting that high levels of sEng promote metabolic syndrome symptoms and complications. Therefore, we suggest that the treatment of metabolic syndrome should take into account the importance of Eng in the endothelial function and levels of sEng as a biomarker and risk factor of related pathologies.
- MeSH
- Atherosclerosis metabolism pathology MeSH
- Biomarkers metabolism MeSH
- Cell Membrane metabolism MeSH
- Diabetes Mellitus, Type 2 metabolism pathology MeSH
- Endoglin chemistry metabolism MeSH
- Gene Expression MeSH
- Cardiovascular Diseases metabolism pathology MeSH
- Humans MeSH
- Metabolic Syndrome metabolism pathology MeSH
- Nitric Oxide Synthase Type III metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH