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Andrew D Blann - One of the best experts on this subject based on the ideXlab platform.

  • abnormal Angiopoietins 1 2 Angiopoietin Receptor tie 2 and vascular endothelial growth factor levels in hypertension relationship to target organ damage a sub study of the anglo scandinavian cardiac outcomes trial ascot
    Journal of Internal Medicine, 2005
    Co-Authors: Sunil Nadar, Andrew D Blann, D G Beevers
    Abstract:

    . Background.  The increased risk of target organ damage (TOD) in hypertension may be related to a prothrombotic or hypercoagulable state, with abnormalities in platelet activation. Altered angiogenesis, possibly related to increased plasma vascular endothelial growth factor (VEGF) is also a feature of hypertension. We hypothesized a link between altered angiogenesis and TOD in hypertension. Accordingly, the angiogenic growth factors VEGF, Angiopoietin 1 and 2 (Ang 1 & 2) and soluble Angiopoietin Receptor Tie-2 in plasma and in platelets were assessed in terms of the presence or absence of hypertensive TOD. Methods.  We studied 199 patients (75% men; mean age 68 years) with hypertension. Of these, 125 had evidence of hypertensive TOD (stroke, previous myocardial infarction, angina, left ventricular hypertrophy and mild renal failure). Patients were compared with 74 healthy normotensive controls (69% men; mean age 68 years). Plasma VEGF, Ang 1 & 2 and Tie-2, and total platelet levels of VEGF and Ang-1 (obtained by lysing a known number of platelets with 0.5% Tween) were measured by an enzyme-linked immunosorbent assay. Results.  Hypertensive patients had higher levels of plasma VEGF, Ang-1, Ang-2, Tie-2 and platelet VEGF (all P ≤ 0.01), but not platelet Ang-1, when compared with normotensive controls. Patients with TOD had higher levels of platelet VEGF and Ang-1 (both P < 0.001), and plasma Ang-1 (P < 0.001). Amongst the hypertensives, plasma levels of VEGF correlated significantly with Ang-1, Ang-2, Tie-2 and platelet VEGF, whilst platelet VEGF correlated strongly with plasma levels of VEGF and Ang-1 (all P < 0.05). Conclusion.  Patients with hypertension have evidence of changes in plasma angiogenic growth factors that correlate with the platelet levels of these molecules. Platelets may be involved in the abnormal angiogenesis seen in hypertension.

  • plasma vascular endothelial growth factor Angiopoietin 2 and soluble Angiopoietin Receptor tie 2 in diabetic retinopathy effects of laser photocoagulation and angiotensin Receptor blockade
    British Journal of Ophthalmology, 2004
    Co-Authors: Pecklin Lip, Andrew D Blann, S Chatterjee, G J Caine, M Hopeross, Jonathan Gibson, Gregory Y H Lip
    Abstract:

    Background: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), Angiopoietin-2 (Ang-2), and the soluble Angiopoietin Receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin Receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. Methods: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. Results: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. Conclusion: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the Angiopoietin/tie-2 system in this condition.

  • plasma Angiopoietin 1 Angiopoietin 2 Angiopoietin Receptor tie 2 and vascular endothelial growth factor levels in acute coronary syndromes
    Circulation, 2004
    Co-Authors: Andrew D Blann
    Abstract:

    Background— Angiopoietin (Ang) -1 and -2, their Receptor Tie-2, and vascular endothelial growth factor (VEGF) regulate angiogenesis and may be important in myocardial collateral development. Elevated levels of growth factors and their Receptors are reported in myocardial infarction (MI), but changes after an acute coronary event are unknown. Methods and Results— Plasma Ang-1, Ang-2, Tie-2, and VEGF levels were measured on admission (baseline) and at 48 hours (acute stage) in 126 patients with acute coronary syndrome (82 MI, 44 unstable angina pectoris). Baseline levels were compared with those of 40 patients with stable angina and 40 healthy controls. Measurements were repeated in 38 MI patients at 6 and 18 weeks (chronic stage). Baseline Ang-2 and Tie-2 levels were highest in MI patients (P<0.001). Patients with MI and unstable angina pectoris had higher VEGF levels compared with stable angina patients and healthy control subjects (P<0.001). In patients with acute MI, serial changes in all indexes from b...

  • Plasma Angiopoietin-1, Angiopoietin-2, and Angiopoietin Receptor tie-2 levels in congestive heart failure
    Journal of the American College of Cardiology, 2004
    Co-Authors: Aun-yeong Chong, Graham J. Caine, Bethan Freestone, Andrew D Blann
    Abstract:

    Abstract Objectives The goal of this research was to test the hypothesis that plasma Angiopoietin (Ang-1), its soluble Receptor tie-2, and Ang-2 levels would be abnormal in patients with acute and chronic congestive heart failure (CHF) when compared with healthy controls. Background Increased plasma vascular endothelial growth factor (VEGF) in CHF is suggestive of excess angiogenesis—possibly driven by tissue hypoxia. However, other growth factors also have a major role in angiogenesis, such as those of the Angiopoietin family (e.g., Ang-1, which exerts its activity via its Receptor, tie-2, and Ang-2). Methods We recruited 39 patients with acute CHF (mean age 67 ± 10 years), 40 patients with chronic CHF (mean age 63 ± 9 years), and 17 healthy controls (mean age 67 ± 7 years), all in sinus rhythm. Citrated plasma was analyzed for Ang-1, Ang-2, tie-2, and VEGF by enzyme-linked immunosorbent assay. Results Angiopoietin-2 (p Conclusions We have demonstrated abnormal levels of Ang-2 and tie-2, but normal Ang-1, in both CHF patients. These abnormalities may, alongside VEGF, indicate a role for these angiogenic factors in the pathophysiology of CHF.

Gantenbein Benjamin - One of the best experts on this subject based on the ideXlab platform.

  • Spheroid-like Cultures for Cell Expansion of Angiopoietin Receptor-1 (aka. Tie2) positive Cells from the human Intervertebral Disc
    AO Foundation, 2020
    Co-Authors: Zhang Xingshuo, Guerrero Julien, Häckel Sonja, Croft, Andreas Shaun, Graf Selianne, Oberli Andrea, Sakai Daisuke, Tryfonidou Marianna, Benneker, Lorin Michael, Gantenbein Benjamin
    Abstract:

    INTRODUCTION:Low back pain is the leading cause of disability worldwide (1). Nevertheless, the mechanism of the intervertebral disc (IVD) degeneration is still not clear. In this context, the nucleus pulposus (NP) and more precisely NP progenitor cells (NPPCs) present in the IVD, positive for Angiopoietin-1 Receptor (aka. Tie2) display multipotent and stem capacity (2,3). In this study, the first aim was to determine whether spheroid formation in suspension-culture will increase the amount/percentage of NPPCs during the expansion compared to traditional monolayer culture. The second aim of this study was to investigate if the percentage of NPPCs will be enriched even further by the resuspension of the spheroid-like cultured cells (=1st generation) and reformation of those spheroids one more time (= 2nd generation). METHODS:Human NP tissues from trauma patients (N=3) were obtained with written ethical consent and isolated by a two-step digestion protocol (3). The NP cells were resuspended and frozen at -150°C after reaching confluence of passage 0. At passage 1, NP cells were seeded in standard or ultra-low attachment tissue culture flasks with 2.5 ng/ml FGF-2 in low glucose - DMEM (supplemented with 10 % FBS). Flow cytometry was used to analyze and quantify the percentage of NPPCs using Tie2 antibody. We defined the spheroids formed after passage 1 NPCs as 1st generation spheroid. We obtained the 2nd generation spheroids by resuspending the 1st-generation-spheroid and reassembly. The NPCs from 1st and 2nd spheroid were quantified by CFU-assay. RESULTS:As a result, the percentage of NPPCs in monolayer culture condition was reaching 7 ± 2 % (Mean±SEM), however, in the 1st and 2nd generation spheroids culture condition, we were observing 20 ± 10 % and 28 ± 6% of Tie2+ cells, respectively. Concerning the CFU-assay, the NPCs from the 2nd generation spheroid formed 30 CFU-S per 1,000 cells, which were twice more CFU-S compared to the 1st generation spheroid. DISCUSSION & CONCLUSIONS:From these data we conclude than the spheroid-like formation of NPCs would be a more efficient method for expansion and enrichment of NPPCs than monolayer expansion in a context of future cell therapy. Acknowledgements:Financial support was received from iPSpine H2020 project under grant agreement #825925 and China Scholarship Council to X.Z

  • Spheroid-Like Cultures for Expanding Angiopoietin Receptor-1 (aka. Tie2) Positive Cells from the Human Intervertebral Disc.
    'MDPI AG', 2020
    Co-Authors: Zhang Xingshuo, Guerrero Julien, Häckel Sonja, Croft, Andreas S., Albers, Christoph E., Gantenbein Benjamin
    Abstract:

    Lower back pain is a leading cause of disability worldwide. The recovery of nucleus pulposus (NP) progenitor cells (NPPCs) from the intervertebral disc (IVD) holds high promise for future cell therapy. NPPCs are positive for the Angiopoietin-1 Receptor (Tie2) and possess stemness capacity. However, the limited Tie2+ NPC yield has been a challenge for their use in cell-based therapy for regenerative medicine. In this study, we attempted to expand NPPCs from the whole NP cell population by spheroid-formation assay. Flow cytometry was used to quantify the percentage of NPPCs with Tie2-antibody in human primary NP cells (NPCs). Cell proliferation was assessed using the population doublings level (PDL) measurement. Synthesis and presence of extracellular matrix (ECM) from NPC spheroids were confirmed by quantitative Polymerase Chain Reaction (qPCR), immunostaining, and microscopy. Compared with monolayer, the spheroid-formation assay enriched the percentage of Tie2+ in NPCs' population from ~10% to ~36%. Moreover, the spheroid-formation assay also inhibited the proliferation of the Tie2- NPCs with nearly no PDL. After one additional passage (P) using the spheroid-formation assay, NPC spheroids presented a Tie2+ percentage even further by ~10% in the NPC population. Our study concludes that the use of a spheroid culture system could be successfully applied to the culture and expansion of tissue-specific progenitors

  • Can PPARδ agonist increase cell yield of nucleus pulposus progenitor cells positive for Angiopoietin-1 Receptor (= TIE2) after cell isolation?
    2019
    Co-Authors: Zhang Xingshuo, Sakai Daisuke, Tryfonidou Marianna, Frauchiger, Daniela A., May, Rahel D., Dzafo Emina, Tekari Adel, Benneker, Lorin M., Gantenbein Benjamin
    Abstract:

    Introduction: Nucleus pulposus progenitor cells (NPPC), Tie2+ cells (positive for Angiopoietin Receptor), which possess multi-lineage differential potential is a potential cell population for cell therapy. However, the number of Tie2+ cells in NP is extremely limited. Referring to the recent research of Tie2+ hematopoietic stem cells we attempted to increase the Tie2+ cell sub-population in nucleus pulposus cells (NPC) by PPARδ agonist treatment and increasing mitophagy. Methods: Cells were isolated from fresh human IVD tissue from spinal surgery with written consent. The passage 1 human NP cells were cultured in low glucose Dulbecco’s Modified Eagle’s Medium media containing PPARδ agonist (GW501516, Sigma), i.e., 25 µM, or vehicle control (N = 2 donors). After 10 days NP, the Tie2 marker expression was then detected by flow cytometry cells and relative gene expression was determined by real-time qPCR, i.e. at ACAN, col1, col2, and PTEN-induced kinase 1 (PINK1). Results: PPARδ-agonist-treated NP population had ~3 times more Tie2+ cells and PINK1 gene expression tended to be higher than in the vehicle control group. Conclusion: PPARδ agonist possibly increases the Tie2+ cell population in NPC by increasing mitophagy similar to hematopoietic stem cells

Sebastian Maurerstroh - One of the best experts on this subject based on the ideXlab platform.

  • Angiopoietin Receptor tek mutations underlie primary congenital glaucoma with variable expressivity
    Journal of Clinical Investigation, 2016
    Co-Authors: Tomokazu Souma, Stuart W Tompson, Benjamin R Thomson, Krishnakumar Kizhatil, Kristina N Whisenhunt, Owen M Siggs, Vachiranee Limviphuvadh, Shinji Yamaguchi, Liang Feng, Sebastian Maurerstroh
    Abstract:

    Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional Angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm’s canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in Angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.

Gregory Y H Lip - One of the best experts on this subject based on the ideXlab platform.

  • plasma vascular endothelial growth factor Angiopoietin 2 and soluble Angiopoietin Receptor tie 2 in diabetic retinopathy effects of laser photocoagulation and angiotensin Receptor blockade
    British Journal of Ophthalmology, 2004
    Co-Authors: Pecklin Lip, Andrew D Blann, S Chatterjee, G J Caine, M Hopeross, Jonathan Gibson, Gregory Y H Lip
    Abstract:

    Background: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), Angiopoietin-2 (Ang-2), and the soluble Angiopoietin Receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin Receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. Methods: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. Results: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. Conclusion: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the Angiopoietin/tie-2 system in this condition.

Shinji Yamaguchi - One of the best experts on this subject based on the ideXlab platform.

  • ascending vasa recta are Angiopoietin tie2 dependent lymphatic like vessels
    Journal of The American Society of Nephrology, 2017
    Co-Authors: Yael Kenigkozlovsky, Rizaldy P Scott, Isabel Anna Carota, Christine E Tanna, Benjamin R Thomson, Tuncer Onay, Veronica Ramirez, Shinji Yamaguchi, Stefan Heinen, Christine Wu
    Abstract:

    Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the Angiopoietin Receptor endothelial tyrosine kinase 2 (Tie2) or both Angiopoietin-1 and Angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal Angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor Receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle–associated protein). Taken together, our data redefine the AVRs as Tie2 signaling–dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.

  • Angiopoietin Receptor tek mutations underlie primary congenital glaucoma with variable expressivity
    Journal of Clinical Investigation, 2016
    Co-Authors: Tomokazu Souma, Stuart W Tompson, Benjamin R Thomson, Krishnakumar Kizhatil, Kristina N Whisenhunt, Owen M Siggs, Vachiranee Limviphuvadh, Shinji Yamaguchi, Liang Feng, Sebastian Maurerstroh
    Abstract:

    Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional Angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm’s canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in Angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.