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Hetty C De Boer - One of the best experts on this subject based on the ideXlab platform.

  • the role of microRNA 126 in vascular homeostasis
    Current Vascular Pharmacology, 2015
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Hetty C De Boer, Ton J Rabelink, Anton Jan Van Zonneveld
    Abstract:

    microRNAs are negative regulators of gene expression that have been shown to be essential elements in the coordination of complex regulatory pathways. One of these short non-coding RNAs, microRNA-126, is highly enriched in the vascular endothelium and was shown to play distinct roles in angiogenesis, vasculogenesis and endothelial inflammation. Abrogation of this microRNA leads to severe complications in the response in vascular development as well as vital repair mechanisms carried out by endothelial cells. Interestingly, recent data suggest that the homeostatic role of microRNA-126 may reach far beyond its endothelial functions as this microRNA was also found to be present in cells of the hematopoietic system and in microvesicles or 'free-form' in the periphery. microRNA-126 is controlling the fate and/or function of a variety of cells differentiating from the hematopoietic lineage, including megakaryocytes and erythrocytes. Recent studies identified circulating microRNA-126 as a biomarker for myocardial injury and vascular damage in diabetes. Furthermore, reports have suggested a protective role of circulating microRNA-126 in murine models of organ ischemia. Here, we review current insights in the role of microRNA-126 in vascular homeostasis and conclude that this microRNA may serve to integrate and facilitate both local as well as systemic functions in vascular maintenance and repair.

  • hematopoietic microRNA 126 protects against renal ischemia reperfusion injury by promoting vascular integrity
    Journal of The American Society of Nephrology, 2014
    Co-Authors: Roel Bijkerk, Hetty C De Boer, Coen Van Solingen, Pieter Van Der Pol, Meriem Khairoun, Ruben G De Bruin, Annemarie M Van Oeverenrietdijk, Ellen Lievers, Nicole Schlagwein, Danielle J Van Gijlswijk
    Abstract:

    Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. microRNA-126 (miR-126) facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin(-)/Sca-1(+)/cKit(+) hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin(-)/Sca-1(+)/cKit(+) cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin(-)/Sca-1(+)/cKit(+) cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

  • aspirin treatment hampers the use of plasma microRNA 126 as a biomarker for the progression of vascular disease
    European Heart Journal, 2013
    Co-Authors: Hetty C De Boer, Jacques M G J Duijs, Coen Van Solingen, Ton J Rabelink, Jurrien Prins, Menno V Huisman, Anton Jan Van Zonneveld
    Abstract:

    Aims microRNA-126 (miR-126) facilitates angiogenesis and regulates endothelial cell function. Recent data suggest that miR-126 can serve as a biomarker for vascular disease. Although endothelial cells are enriched for miR-126, platelets also contain miR-126. In this paper, we investigated the contribution of platelets to the pool of miR-126 in plasma of patients with type 2 diabetes (DM2) and how this is affected by aspirin. Methods and results In vitro platelet activation resulted in the transfer of miR-126 from the platelet to the plasma compartment, which was prevented by aspirin. In vivo platelet activation, monitored in patients with DM2 by measuring soluble P-selectin, correlated directly with circulating levels of miR-126. The administration of aspirin resulted both in platelet inhibition and concomitantly reduced circulating levels of platelet-derived microRNAs including miR-126. Conclusion Platelets are a major source of circulating miR-126. Consequently, in patho-physiological conditions associated with platelet activation, such as diabetes type 2, the administration of aspirin may lead to reduced levels of circulating miR-126. Thus, the use of platelet inhibitors should be taken into account when using plasma levels of miR-126 as a biomarker.

  • microRNA 126 modulates endothelial sdf 1 expression and mobilization of sca 1 lin progenitor cells in ischaemia
    Cardiovascular Research, 2011
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Matthieu Monge, Paul H A Quax, Hetty C De Boer, Annemarie M Van Oeverenrietdijk, Margreet R De Vries, Van Der Veer Eric Peter, Ton J Rabelink
    Abstract:

    Aims microRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1). Methods and results Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro . Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1+/Lin− progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals. Conclusion miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1+/Lin− progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.

  • antagomir mediated silencing of endothelial cell specific microRNA 126 impairs ischemia induced angiogenesis
    Journal of Cellular and Molecular Medicine, 2009
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Jacques M G J Duijs, Marko K Roeten, Annemarie M Van Oeverenrietdijk, Matthieu Monge, Hetty C De Boer, Hans J Baelde, Paul H A Quax
    Abstract:

    microRNAs are negative regulators of gene expression that play a key role in cell-type specific differentiation and modulation of cell function and have been proposed to be involved in neovascularization. Previously, using an extensive cloning and sequencing approach, we identified miR-126 to be specifically and highly expressed in human endothelial cells (EC). Here, we demonstrate EC-specific expression of miR-126 in capillaries and the larger vessels in vivo. We therefore explored the potential role of miR-126 in arteriogenesis and angiogenesis. Using miR-reporter constructs, we show that miR-126 is functionally active in EC in vitro and that it could be specifically repressed using antagomirs specifically targeting miR-126. To study the consequences of miR-126 silencing on vascular regeneration, mice were injected with a single dose of antagomir-126 or a control ‘scramblemir’ and exposed to ischemia of the left hindlimb by ligation of the femoral artery. Although miR-126 was effectively silenced in mice treated with a single, high dose (HD) of antagomir-126, laser Doppler perfusion imaging did not show effects on blood flow recovery. In contrast, quantification of the capillary density in the gastrocnemius muscle revealed that mice treated with a HD of antagomir-126 had a markedly reduced angiogenic response. Aortic explant cultures of the mice confirmed the role of miR-126 in angiogenesis. Our data demonstrate a facilitary function for miR-126 in ischemia-induced angiogenesis and show the efficacy and specificity of antagomir-induced silencing of EC-specific microRNAs in vivo.

Anders Jakobsen - One of the best experts on this subject based on the ideXlab platform.

  • changes in circulating microRNA 126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer
    British Journal of Cancer, 2015
    Co-Authors: Torben Hansen, Flemming Brandt Sørensen, Anting Liu Carlsen, Niels H H Heegaard, Anders Jakobsen
    Abstract:

    This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab. The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT–PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS). Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050–0.565) compared with a median decrease of −0.374 (95% CI, −0.472 to −0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33–1.09), P=0.07. The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments.

  • intra tumoural vessel area estimated by expression of epidermal growth factor like domain 7 and microRNA 126 in primary tumours and metastases of patients with colorectal cancer a descriptive study
    Journal of Translational Medicine, 2015
    Co-Authors: Torben Hansen, Boye Schnack Nielsen, Anders Jakobsen, Flemming Brandt Sørensen
    Abstract:

    Understanding the biological properties of potential drug targets are important. This is especially true for anti-angiogenic therapies in the search for potential biomarkers. The aim of the present descriptive study was to analyse the intra-tumoural expressions of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miRNA-126) in primary tumours from patients with stage II-IV colorectal cancer (CRC) and in paired samples of primary tumours, regional lymph node metastases and distant metastases. A total of 126 patients were included. Analyses were performed on resections of primary tumours, regional lymph node metastases, and large needle biopsies from distant metastases. EGFL7 was analysed by immunohistochemistry (IHC) and miRNA-126 by in situ hybridization (ISH). Both biomarkers were quantified by image guided analyses to determine the relative fraction estimates of vessel areas (VA). The intra-tumoural EGFL7 VA was significantly higher in primary tumours from patients with recurrent disease than in patients without relapse in both stage II and III, p = 0.019 and p = 0.001, respectively. The EGFL7 VA was significantly higher and the miRNA-126 VA significantly lower in regional lymph node metastases compared to primary tumours, p = 0.01 and p < 10−6, respectively. Furthermore, the miRNA-126 VA in liver metastases was significantly lower than in the primary tumours, p = 0.02. The intra-tumoural expression of EGFL7 in early stages of CRC may influence the risk of post-surgical recurrence. Differential expression of miRNA-126 seems more pronounced in disseminated disease, which supports its role as a regulator in the metastatic process.

  • Abstract LB-174: microRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer
    Cancer Research, 2014
    Co-Authors: Boye Schnack Nielsen, Flemming Brandt Sørensen, Anders Jakobsen, Anders Johnsson, Torben Hansen
    Abstract:

    The miR-126 gene is located within intron 7 of the EGFL7 encoding gene, and therefore miR-126 expression is dependent on the transcription of the EGFL7 gene. It has been suggested that transcription is regulated by the VEGFR pathway through Ets1 transcription factor, that miR-126 itself negatively regulates the VEGF-R signaling pathway, and that EGFL7 itself regulates Notch signaling. In cancer therapeutic settings, VEGF or VEGF-R directed therapies are thus likely to affect expression of EGFL7 and miR-126. In colorectal cancer (CRC) tissue, miR-126 and EGFL7 are highly expressed in endothelial cells. In studies of XELOX-treated patients, we have previously reported that the miR-126 expression level measured by quantitative in situ hybridization (qISH) is related to poor response (Hansen et al, BMC Cancer 2012, 12:83). Here, we have analyzed miR-126 and EGFL7 expression by qISH and quantitative immunohistochemistry (qIHC), respectively, in 158 patients from two different cohorts with mCRC after treatment with anti-VEGF therapy (Bevacizumab) in combination with chemotherapy. We found that the EGFL7 vessel area (VA) in primary tumors was closely related to treatment response with a median EGFL7 VA in responding patients of 4 (95% CI 4-6) compared to 8.5 (95% CI 7-11) in non-responders, p Citation Format: Boye S. Nielsen, Flemming B. Sorensen, Anders Johnsson, Anders Jakobsen, Torben F. Hansen. microRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2014-LB-174

  • the prognostic value of microRNA 126 and microvessel density in patients with stage ii colon cancer results from a population cohort
    Journal of Translational Medicine, 2014
    Co-Authors: Torben Hansen, Anders Jakobsen, Jan Lindebjerg, Sanne Kjaerfrifeldt, Soren Morgenthaler, Thorarinn Blondal, Flemming Brandt Sørensen
    Abstract:

    Angiogenesis plays a pivotal role in malignant tumour growth and the metastatic process. We analysed the prognostic value of two angiogenesis parameters, microRNA-126 (miRNA-126) and microvessel density (MVD), in a population based cohort of patients operated for stage II colon cancer. A total of 560 patients were included. Analyses were performed on formalin fixed paraffin embedded tissue from the primary tumours. The analysis of miRNA-126 expression was performed by qPCR. Microvessels were visualised by CD105 and quantified in hot spots using a light microscope. The analyses were correlated with recurrence-free cancer specific survival (RF-CSS) and overall survival (OS). Low miRNA-126 expression was significantly correlated to T4, high malignancy grade, tumour perforation, fixation, and the presence of microsatellite instability. A prognostic impact on OS was detected in the simple analysis favouring patients with high miRNA-126 expression p = 0.03, and borderline significance as to RF-CSS, p = 0.08. The impact on OS demonstrated borderline significance in a following multiple Cox regression analysis, hazard ratio 0.76 (95% confidence interval, 0.58-1.00), p = 0.051. The MVD estimate was not associated with either RF-CSS, p = 0.49, or OS, p = 0.94. The current population based study of patients operated for stage II colon cancer demonstrated correlations between several prognostic unfavourable characteristics and miRNA-126 and argues for a possible prognostic impact on overall survival. An influence on survival by the MVD estimate was not detected.

  • microRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial.
    British Journal of Cancer, 2013
    Co-Authors: Torben Hansen, Rikke Fredslund Andersen, R. Dp Christensen, Flemming Brandt Sørensen, Anders Johnsson, Anders Jakobsen
    Abstract:

    Background: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. Results: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio = 0.49, 95% confidence interval = 0.29-0.84, P = 0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P = 0.063). Conclusion: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics. (Less)

Coen Van Solingen - One of the best experts on this subject based on the ideXlab platform.

  • the role of microRNA 126 in vascular homeostasis
    Current Vascular Pharmacology, 2015
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Hetty C De Boer, Ton J Rabelink, Anton Jan Van Zonneveld
    Abstract:

    microRNAs are negative regulators of gene expression that have been shown to be essential elements in the coordination of complex regulatory pathways. One of these short non-coding RNAs, microRNA-126, is highly enriched in the vascular endothelium and was shown to play distinct roles in angiogenesis, vasculogenesis and endothelial inflammation. Abrogation of this microRNA leads to severe complications in the response in vascular development as well as vital repair mechanisms carried out by endothelial cells. Interestingly, recent data suggest that the homeostatic role of microRNA-126 may reach far beyond its endothelial functions as this microRNA was also found to be present in cells of the hematopoietic system and in microvesicles or 'free-form' in the periphery. microRNA-126 is controlling the fate and/or function of a variety of cells differentiating from the hematopoietic lineage, including megakaryocytes and erythrocytes. Recent studies identified circulating microRNA-126 as a biomarker for myocardial injury and vascular damage in diabetes. Furthermore, reports have suggested a protective role of circulating microRNA-126 in murine models of organ ischemia. Here, we review current insights in the role of microRNA-126 in vascular homeostasis and conclude that this microRNA may serve to integrate and facilitate both local as well as systemic functions in vascular maintenance and repair.

  • hematopoietic microRNA 126 protects against renal ischemia reperfusion injury by promoting vascular integrity
    Journal of The American Society of Nephrology, 2014
    Co-Authors: Roel Bijkerk, Hetty C De Boer, Coen Van Solingen, Pieter Van Der Pol, Meriem Khairoun, Ruben G De Bruin, Annemarie M Van Oeverenrietdijk, Ellen Lievers, Nicole Schlagwein, Danielle J Van Gijlswijk
    Abstract:

    Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. microRNA-126 (miR-126) facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin(-)/Sca-1(+)/cKit(+) hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin(-)/Sca-1(+)/cKit(+) cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin(-)/Sca-1(+)/cKit(+) cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

  • aspirin treatment hampers the use of plasma microRNA 126 as a biomarker for the progression of vascular disease
    European Heart Journal, 2013
    Co-Authors: Hetty C De Boer, Jacques M G J Duijs, Coen Van Solingen, Ton J Rabelink, Jurrien Prins, Menno V Huisman, Anton Jan Van Zonneveld
    Abstract:

    Aims microRNA-126 (miR-126) facilitates angiogenesis and regulates endothelial cell function. Recent data suggest that miR-126 can serve as a biomarker for vascular disease. Although endothelial cells are enriched for miR-126, platelets also contain miR-126. In this paper, we investigated the contribution of platelets to the pool of miR-126 in plasma of patients with type 2 diabetes (DM2) and how this is affected by aspirin. Methods and results In vitro platelet activation resulted in the transfer of miR-126 from the platelet to the plasma compartment, which was prevented by aspirin. In vivo platelet activation, monitored in patients with DM2 by measuring soluble P-selectin, correlated directly with circulating levels of miR-126. The administration of aspirin resulted both in platelet inhibition and concomitantly reduced circulating levels of platelet-derived microRNAs including miR-126. Conclusion Platelets are a major source of circulating miR-126. Consequently, in patho-physiological conditions associated with platelet activation, such as diabetes type 2, the administration of aspirin may lead to reduced levels of circulating miR-126. Thus, the use of platelet inhibitors should be taken into account when using plasma levels of miR-126 as a biomarker.

  • microRNA 126 modulates endothelial sdf 1 expression and mobilization of sca 1 lin progenitor cells in ischaemia
    Cardiovascular Research, 2011
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Matthieu Monge, Paul H A Quax, Hetty C De Boer, Annemarie M Van Oeverenrietdijk, Margreet R De Vries, Van Der Veer Eric Peter, Ton J Rabelink
    Abstract:

    Aims microRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1). Methods and results Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro . Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1+/Lin− progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals. Conclusion miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1+/Lin− progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.

  • antagomir mediated silencing of endothelial cell specific microRNA 126 impairs ischemia induced angiogenesis
    Journal of Cellular and Molecular Medicine, 2009
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Jacques M G J Duijs, Marko K Roeten, Matthieu Monge, Hans J Baelde, Annemarie M Van Oeverenrietdijk, Joost B Vos, Hetty C De Boer
    Abstract:

    microRNAs are negative regulators of gene expression that play a key role in cell-type specific differentiation and modulation of cell function and have been proposed to be involved in neovascularization. Previously, using an extensive cloning and sequencing approach, we identified miR-126 to be specifically and highly expressed in human endothelial cells (EC). Here, we demonstrate EC-specific expression of miR-126 in capillaries and the larger vessels in vivo. We therefore explored the potential role of miR-126 in arteriogenesis and angiogenesis. Using miR-reporter constructs, we show that miR-126 is functionally active in EC in vitro and that it could be specifically repressed using antagomirs specifically targeting miR-126. To study the consequences of miR-126 silencing on vascular regeneration, mice were injected with a single dose of antagomir-126 or a control 'scramblemir' and exposed to ischemia of the left hindlimb by ligation of the femoral artery. Although miR-126 was effectively silenced in mice treated with a single, high dose (HD) of antagomir-126, laser Doppler perfusion imaging did not show effects on blood flow recovery. In contrast, quantification of the capillary density in the gastrocnemius muscle revealed that mice treated with a HD of antagomir-126 had a markedly reduced angiogenic response. Aortic explant cultures of the mice confirmed the role of miR-126 in angiogenesis. Our data demonstrate a facilitary function for miR-126 in ischemia-induced angiogenesis and show the efficacy and specificity of antagomir-induced silencing of EC-specific microRNAs in vivo. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Torben Hansen - One of the best experts on this subject based on the ideXlab platform.

  • changes in circulating microRNA 126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer
    British Journal of Cancer, 2015
    Co-Authors: Torben Hansen, Flemming Brandt Sørensen, Anting Liu Carlsen, Niels H H Heegaard, Anders Jakobsen
    Abstract:

    This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab. The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT–PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS). Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050–0.565) compared with a median decrease of −0.374 (95% CI, −0.472 to −0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33–1.09), P=0.07. The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments.

  • intra tumoural vessel area estimated by expression of epidermal growth factor like domain 7 and microRNA 126 in primary tumours and metastases of patients with colorectal cancer a descriptive study
    Journal of Translational Medicine, 2015
    Co-Authors: Torben Hansen, Boye Schnack Nielsen, Anders Jakobsen, Flemming Brandt Sørensen
    Abstract:

    Understanding the biological properties of potential drug targets are important. This is especially true for anti-angiogenic therapies in the search for potential biomarkers. The aim of the present descriptive study was to analyse the intra-tumoural expressions of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miRNA-126) in primary tumours from patients with stage II-IV colorectal cancer (CRC) and in paired samples of primary tumours, regional lymph node metastases and distant metastases. A total of 126 patients were included. Analyses were performed on resections of primary tumours, regional lymph node metastases, and large needle biopsies from distant metastases. EGFL7 was analysed by immunohistochemistry (IHC) and miRNA-126 by in situ hybridization (ISH). Both biomarkers were quantified by image guided analyses to determine the relative fraction estimates of vessel areas (VA). The intra-tumoural EGFL7 VA was significantly higher in primary tumours from patients with recurrent disease than in patients without relapse in both stage II and III, p = 0.019 and p = 0.001, respectively. The EGFL7 VA was significantly higher and the miRNA-126 VA significantly lower in regional lymph node metastases compared to primary tumours, p = 0.01 and p < 10−6, respectively. Furthermore, the miRNA-126 VA in liver metastases was significantly lower than in the primary tumours, p = 0.02. The intra-tumoural expression of EGFL7 in early stages of CRC may influence the risk of post-surgical recurrence. Differential expression of miRNA-126 seems more pronounced in disseminated disease, which supports its role as a regulator in the metastatic process.

  • Abstract LB-174: microRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer
    Cancer Research, 2014
    Co-Authors: Boye Schnack Nielsen, Flemming Brandt Sørensen, Anders Jakobsen, Anders Johnsson, Torben Hansen
    Abstract:

    The miR-126 gene is located within intron 7 of the EGFL7 encoding gene, and therefore miR-126 expression is dependent on the transcription of the EGFL7 gene. It has been suggested that transcription is regulated by the VEGFR pathway through Ets1 transcription factor, that miR-126 itself negatively regulates the VEGF-R signaling pathway, and that EGFL7 itself regulates Notch signaling. In cancer therapeutic settings, VEGF or VEGF-R directed therapies are thus likely to affect expression of EGFL7 and miR-126. In colorectal cancer (CRC) tissue, miR-126 and EGFL7 are highly expressed in endothelial cells. In studies of XELOX-treated patients, we have previously reported that the miR-126 expression level measured by quantitative in situ hybridization (qISH) is related to poor response (Hansen et al, BMC Cancer 2012, 12:83). Here, we have analyzed miR-126 and EGFL7 expression by qISH and quantitative immunohistochemistry (qIHC), respectively, in 158 patients from two different cohorts with mCRC after treatment with anti-VEGF therapy (Bevacizumab) in combination with chemotherapy. We found that the EGFL7 vessel area (VA) in primary tumors was closely related to treatment response with a median EGFL7 VA in responding patients of 4 (95% CI 4-6) compared to 8.5 (95% CI 7-11) in non-responders, p Citation Format: Boye S. Nielsen, Flemming B. Sorensen, Anders Johnsson, Anders Jakobsen, Torben F. Hansen. microRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2014-LB-174

  • the prognostic value of microRNA 126 and microvessel density in patients with stage ii colon cancer results from a population cohort
    Journal of Translational Medicine, 2014
    Co-Authors: Torben Hansen, Anders Jakobsen, Jan Lindebjerg, Sanne Kjaerfrifeldt, Soren Morgenthaler, Thorarinn Blondal, Flemming Brandt Sørensen
    Abstract:

    Angiogenesis plays a pivotal role in malignant tumour growth and the metastatic process. We analysed the prognostic value of two angiogenesis parameters, microRNA-126 (miRNA-126) and microvessel density (MVD), in a population based cohort of patients operated for stage II colon cancer. A total of 560 patients were included. Analyses were performed on formalin fixed paraffin embedded tissue from the primary tumours. The analysis of miRNA-126 expression was performed by qPCR. Microvessels were visualised by CD105 and quantified in hot spots using a light microscope. The analyses were correlated with recurrence-free cancer specific survival (RF-CSS) and overall survival (OS). Low miRNA-126 expression was significantly correlated to T4, high malignancy grade, tumour perforation, fixation, and the presence of microsatellite instability. A prognostic impact on OS was detected in the simple analysis favouring patients with high miRNA-126 expression p = 0.03, and borderline significance as to RF-CSS, p = 0.08. The impact on OS demonstrated borderline significance in a following multiple Cox regression analysis, hazard ratio 0.76 (95% confidence interval, 0.58-1.00), p = 0.051. The MVD estimate was not associated with either RF-CSS, p = 0.49, or OS, p = 0.94. The current population based study of patients operated for stage II colon cancer demonstrated correlations between several prognostic unfavourable characteristics and miRNA-126 and argues for a possible prognostic impact on overall survival. An influence on survival by the MVD estimate was not detected.

  • microRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial.
    British Journal of Cancer, 2013
    Co-Authors: Torben Hansen, Rikke Fredslund Andersen, R. Dp Christensen, Flemming Brandt Sørensen, Anders Johnsson, Anders Jakobsen
    Abstract:

    Background: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. Results: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio = 0.49, 95% confidence interval = 0.29-0.84, P = 0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P = 0.063). Conclusion: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics. (Less)

Roel Bijkerk - One of the best experts on this subject based on the ideXlab platform.

  • the role of microRNA 126 in vascular homeostasis
    Current Vascular Pharmacology, 2015
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Hetty C De Boer, Ton J Rabelink, Anton Jan Van Zonneveld
    Abstract:

    microRNAs are negative regulators of gene expression that have been shown to be essential elements in the coordination of complex regulatory pathways. One of these short non-coding RNAs, microRNA-126, is highly enriched in the vascular endothelium and was shown to play distinct roles in angiogenesis, vasculogenesis and endothelial inflammation. Abrogation of this microRNA leads to severe complications in the response in vascular development as well as vital repair mechanisms carried out by endothelial cells. Interestingly, recent data suggest that the homeostatic role of microRNA-126 may reach far beyond its endothelial functions as this microRNA was also found to be present in cells of the hematopoietic system and in microvesicles or 'free-form' in the periphery. microRNA-126 is controlling the fate and/or function of a variety of cells differentiating from the hematopoietic lineage, including megakaryocytes and erythrocytes. Recent studies identified circulating microRNA-126 as a biomarker for myocardial injury and vascular damage in diabetes. Furthermore, reports have suggested a protective role of circulating microRNA-126 in murine models of organ ischemia. Here, we review current insights in the role of microRNA-126 in vascular homeostasis and conclude that this microRNA may serve to integrate and facilitate both local as well as systemic functions in vascular maintenance and repair.

  • hematopoietic microRNA 126 protects against renal ischemia reperfusion injury by promoting vascular integrity
    Journal of The American Society of Nephrology, 2014
    Co-Authors: Roel Bijkerk, Hetty C De Boer, Coen Van Solingen, Pieter Van Der Pol, Meriem Khairoun, Ruben G De Bruin, Annemarie M Van Oeverenrietdijk, Ellen Lievers, Nicole Schlagwein, Danielle J Van Gijlswijk
    Abstract:

    Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. microRNA-126 (miR-126) facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin(-)/Sca-1(+)/cKit(+) hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin(-)/Sca-1(+)/cKit(+) cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin(-)/Sca-1(+)/cKit(+) cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

  • microRNA 126 modulates endothelial sdf 1 expression and mobilization of sca 1 lin progenitor cells in ischaemia
    Cardiovascular Research, 2011
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Matthieu Monge, Paul H A Quax, Hetty C De Boer, Annemarie M Van Oeverenrietdijk, Margreet R De Vries, Van Der Veer Eric Peter, Ton J Rabelink
    Abstract:

    Aims microRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1). Methods and results Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro . Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1+/Lin− progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals. Conclusion miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1+/Lin− progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.

  • antagomir mediated silencing of endothelial cell specific microRNA 126 impairs ischemia induced angiogenesis
    Journal of Cellular and Molecular Medicine, 2009
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Jacques M G J Duijs, Marko K Roeten, Annemarie M Van Oeverenrietdijk, Matthieu Monge, Hetty C De Boer, Hans J Baelde, Paul H A Quax
    Abstract:

    microRNAs are negative regulators of gene expression that play a key role in cell-type specific differentiation and modulation of cell function and have been proposed to be involved in neovascularization. Previously, using an extensive cloning and sequencing approach, we identified miR-126 to be specifically and highly expressed in human endothelial cells (EC). Here, we demonstrate EC-specific expression of miR-126 in capillaries and the larger vessels in vivo. We therefore explored the potential role of miR-126 in arteriogenesis and angiogenesis. Using miR-reporter constructs, we show that miR-126 is functionally active in EC in vitro and that it could be specifically repressed using antagomirs specifically targeting miR-126. To study the consequences of miR-126 silencing on vascular regeneration, mice were injected with a single dose of antagomir-126 or a control ‘scramblemir’ and exposed to ischemia of the left hindlimb by ligation of the femoral artery. Although miR-126 was effectively silenced in mice treated with a single, high dose (HD) of antagomir-126, laser Doppler perfusion imaging did not show effects on blood flow recovery. In contrast, quantification of the capillary density in the gastrocnemius muscle revealed that mice treated with a HD of antagomir-126 had a markedly reduced angiogenic response. Aortic explant cultures of the mice confirmed the role of miR-126 in angiogenesis. Our data demonstrate a facilitary function for miR-126 in ischemia-induced angiogenesis and show the efficacy and specificity of antagomir-induced silencing of EC-specific microRNAs in vivo.

  • antagomir mediated silencing of endothelial cell specific microRNA 126 impairs ischemia induced angiogenesis
    Journal of Cellular and Molecular Medicine, 2009
    Co-Authors: Coen Van Solingen, Roel Bijkerk, Leonard Seghers, Jacques M G J Duijs, Marko K Roeten, Matthieu Monge, Hans J Baelde, Annemarie M Van Oeverenrietdijk, Joost B Vos, Hetty C De Boer
    Abstract:

    microRNAs are negative regulators of gene expression that play a key role in cell-type specific differentiation and modulation of cell function and have been proposed to be involved in neovascularization. Previously, using an extensive cloning and sequencing approach, we identified miR-126 to be specifically and highly expressed in human endothelial cells (EC). Here, we demonstrate EC-specific expression of miR-126 in capillaries and the larger vessels in vivo. We therefore explored the potential role of miR-126 in arteriogenesis and angiogenesis. Using miR-reporter constructs, we show that miR-126 is functionally active in EC in vitro and that it could be specifically repressed using antagomirs specifically targeting miR-126. To study the consequences of miR-126 silencing on vascular regeneration, mice were injected with a single dose of antagomir-126 or a control 'scramblemir' and exposed to ischemia of the left hindlimb by ligation of the femoral artery. Although miR-126 was effectively silenced in mice treated with a single, high dose (HD) of antagomir-126, laser Doppler perfusion imaging did not show effects on blood flow recovery. In contrast, quantification of the capillary density in the gastrocnemius muscle revealed that mice treated with a HD of antagomir-126 had a markedly reduced angiogenic response. Aortic explant cultures of the mice confirmed the role of miR-126 in angiogenesis. Our data demonstrate a facilitary function for miR-126 in ischemia-induced angiogenesis and show the efficacy and specificity of antagomir-induced silencing of EC-specific microRNAs in vivo. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.