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Wolfgang Schaper - One of the best experts on this subject based on the ideXlab platform.
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lack of ecto 5 nucleotidase cd73 promotes Arteriogenesis
Cardiovascular Research, 2013Co-Authors: Yang Chul Boring, Wolfgang Schaper, Matthias Heil, Ulrich Flogel, Christoph Jacoby, Jurgen SchraderAbstract:Aims Adenosine can stimulate angiogenesis, but its role in the distinct process of Arteriogenesis is unknown. We have previously reported that mice lacking ecto-5′-nucleotidase (CD73−/−) show enhanced monocyte adhesion to the endothelium after ischaemia, which is considered to be an important trigger for Arteriogenesis. Methods and results Hindlimb ischaemia was induced in wild-type (WT) and CD73−/− mice to study the role of extracellularly formed adenosine in Arteriogenesis. Magnetic resonance angiography (MRA) was performed for serial visualization of newly developed vessels at a spatial resolution of 1 nL, and high-energy phosphates (HEP) were quantified by 31P MR spectroscopy (MRS). MRA of CD73−/− mice revealed substantially enhanced collateral artery conductance at day 7 [CD73−/−: 0.73 ± 0.11 a.u. (arbitrary units); WT: 0.44 ± 0.13 a.u.; P < 0.01, n = 6], and MRS of the affected hindlimb showed a faster restoration of HEP in correlation with enhanced functional recovery in the mutant. Additionally, histology showed no differences in capillary density between the groups but showed an increased monocyte infiltration in hindlimbs of CD73−/− mice. Conclusion Serial assessment of dynamic changes of vessel growth and metabolism in the process of Arteriogenesis demonstrate that the lack of CD73-derived adenosine importantly promotes Arteriogenesis but does not alter angiogenesis in our model of hindlimb ischaemia.
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Arteriogenesis versus angiogenesis in peripheral artery disease
Diabetes-metabolism Research and Reviews, 2012Co-Authors: Kerstin Troidl, Wolfgang SchaperAbstract:Different forms of vessel growth in the adult organism contribute to the compensation for an occluded artery. We here summarize the major differences between Arteriogenesis and angiogenesis and provide evidence in favour of a therapeutic stimulation of collateral growth. In addition, we outline current knowledge about regulatory mechanisms transducing the initial physical stimulus into a cellular response. As an example, the role of nitric oxide during Arteriogenesis is discussed, and finally, we propose a mechanism of how an efficient decision is made that makes the larger collaterals larger and the smaller ones smaller.
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cerebral Arteriogenesis is enhanced by pharmacological as well as fluid shear stress activation of the trpv4 calcium channel
European Journal of Vascular and Endovascular Surgery, 2011Co-Authors: Wilma Schierling, Kerstin Troidl, Wolfgang Schaper, H Apfelbeck, Christian Troidl, Piotr M Kasprzak, Thomas SchmitzrixenAbstract:Abstract Objectives This study aimed to determine the importance of the shear-stress-sensitive calcium channels Trpc1, Trpm7, Trpp2, Trpv2 (transient receptor potential cation channel, subfamily V, member 2) and Trpv4 for cerebral Arteriogenesis. The expression profiles were analysed, comparing the stimulation of collateral growth by target-specific drugs to that achieved by maximum increased fluid shear stress (FSS). Design A prospective, controlled study wherein rats were subjected to bilateral carotid artery ligature (BCL), or BCL + arteriovenous fistula, or BCL + drug application. Methods Messenger RNA (mRNA) abundance and protein expression were determined in FSS-stimulated cerebral collaterals by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Drugs were applied via osmotic mini pumps and Arteriogenesis was evaluated by post-mortem angiograms and Ki67 immunostaining. Results Trpv4 was the only mechanosensitive Trp channel showing significantly increased mRNA abundance and protein expression after FSS stimulation. Activation of Trpv4 by 4α-phorbol-12,13-didecanoate caused significantly enhanced collateral growth (length: 4.43 ± 0.20 mm and diameter: 282.6 ± 8.1 μm) compared with control (length: 3.80 ± 0.06 mm and diameter: 237.3 ± 5.3 μm). Drug application stimulated Arteriogenesis to almost the same extent as did maximum FSS stimulation (length: 4.61 ± 0.07 mm and diameter: 327.4 ± 12.6 μm). Conclusions Trpv4 showed significantly increased expression in FSS-stimulated cerebral collaterals. Pharmacological Trpv4 activation enhanced cerebral Arteriogenesis, pinpointing Trpv4 as a possible candidate for the development of new therapeutic concepts.
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effects of endogenous nitric oxide and of deta nonoate in Arteriogenesis
Journal of Cardiovascular Pharmacology, 2010Co-Authors: Kerstin Troidl, Thomas Schmitzrixen, Weijun Cai, Silvia Tribulova, Inka Ruding, H Apfelbeck, Wilma Schierling, Christian Troidl, Wolfgang SchaperAbstract:Previous studies showed that targeted endothelial nitric oxide synthase (eNOS) disruption in mice with femoral artery occlusion does not impede and transgenic eNOS overexpression does not stimulate collateral artery growth after femoral artery occlusion, suggesting that nitric oxide from eNOS does not play a role in Arteriogenesis. However, pharmacologic nitric oxide synthase inhibition with L-NAME markedly blocks Arteriogenesis, suggestive of an important role of nitric oxide. To solve the paradox, we studied targeted deletion of eNOS and of inducible nitric oxide synthase (iNOS) in mice and found that only iNOS knockout could partially inhibit Arteriogenesis. However, the combination of eNOS knockout and treatment with the iNOS inhibitor L-NIL completely abolished Arteriogenesis. mRNA transcription studies (reverse transcriptase-polymerase chain reaction) performed on collateral arteries of rats showed that eNOS and especially iNOS (but not neural nitric oxide synthase) become upregulated in shear stress-stimulated collateral vessels, which supports the hypothesis that nitric oxide is necessary for Arteriogenesis but that iNOS plays an important part. This was strengthened by the observation that the nitric oxide donor DETA NONOate strongly stimulated collateral artery growth, activated perivascular monocytes, and increased proliferation markers. Shear stress-induced nitric oxide may activate the innate immune system and activate iNOS. In conclusion, Arteriogenesis is completely dependent on the presence of nitric oxide, a large part of it coming from mononuclear cells.
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a critical review of clinical Arteriogenesis research
Journal of the American College of Cardiology, 2009Co-Authors: Niels Van Royen, Wolfgang Schaper, Jan J Piek, William F M FultonAbstract:In human hearts, an extensive pre-existing collateral network is present. This was shown unequivocally some 50 years ago in a series of very detailed post-mortem angiographic studies. In these studies, it was also observed that the pre-existent collateral vessels enlarge upon closure of an epicardial coronary artery, resulting in large collateral conduit arteries, in sharp contrast to earlier claims that human coronary arteries are functional end arteries. These insights still form the basis for the concept of Arteriogenesis as positive remodeling of pre-existent arteriolar connections. Subsequent experimental studies disclosed the putative role of circulating cells, especially monocytes, which invade the proliferating vessel wall and secrete growth factors, degrading enzymes and survival factors that are required for the development of a mature collateral circulation. Experimental stimulation of Arteriogenesis is feasible but to date a relatively low number of clinical studies, with no or limited success, have been performed. The use of intracoronary derived collateral flow index can increase the sensitivity to detect the effects of pharmacological compounds on Arteriogenesis, which is important in first proof-of-principle studies. These invasive measurements also allow the detection of patients with an innate defect in their arteriogenic response to coronary obstruction. In a reversed bedside-to-bench approach, the characterization of ribonucleic acid and protein expression patterns in these patients generated new targets for therapeutic Arteriogenesis.
Kerstin Troidl - One of the best experts on this subject based on the ideXlab platform.
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extracellular rna released due to shear stress controls natural bypass growth by mediating mechanotransduction in mice
Blood, 2019Co-Authors: Manuel Lasch, Silvia Fischer, Thomas Lautz, Eike Kleinert, S Meister, Konda Kumaraswami, Judithirina Buchheim, Tobias Grantzow, Sofia Salpisti, Kerstin TroidlAbstract:Fluid shear stress in the vasculature is the driving force for natural bypass growth, a fundamental endogenous mechanism to counteract the detrimental consequences of vascular occlusive disease, such as stroke or myocardial infarction. This process, referred to as "Arteriogenesis," relies on local recruitment of leukocytes, which supply growth factors to preexisting collateral arterioles enabling them to grow. Although several mechanosensing proteins have been identified, the series of mechanotransduction events resulting in local leukocyte recruitment is not understood. In a mouse model of Arteriogenesis (femoral artery ligation), we found that endothelial cells release RNA in response to increased fluid shear stress and that administration of RNase inhibitor blocking plasma RNases improved perfusion recovery. In contrast, treatment with bovine pancreatic RNase A or human recombinant RNase1 interfered with leukocyte recruitment and collateral artery growth. Our results indicated that extracellular RNA (eRNA) regulated leukocyte recruitment by engaging vascular endothelial growth factor receptor 2 (VEGFR2), which was confirmed by intravital microscopic studies in a murine cremaster model of inflammation. Moreover, we found that release of von Willebrand factor (VWF) as a result of shear stress is dependent on VEGFR2. Blocking VEGFR2, RNase application, or VWF deficiency interfered with platelet-neutrophil aggregate formation, which is essential for initiating the inflammatory process in Arteriogenesis. Taken together, the results show that eRNA is released from endothelial cells in response to shear stress. We demonstrate this extracellular nucleic acid as a critical mediator of mechanotransduction by inducing the liberation of VWF, thereby initiating the multistep inflammatory process responsible for Arteriogenesis.
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midkine controls Arteriogenesis by regulating the bioavailability of vascular endothelial growth factor a and the expression of nitric oxide synthase 1 and 3
EBioMedicine, 2017Co-Authors: Thomas Lautz, Kerstin Troidl, Manuel Lasch, Judith-irina Pagel, Julia Borgolte, Amelia Caballeromartinez, Eike Kleinert, Barbara Walzog, Elisabeth DeindlAbstract:Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in Arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in Arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of Arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.
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Arginase inhibition attenuates Arteriogenesis and interferes with M2 macrophage accumulation
Laboratory Investigation, 2016Co-Authors: Manuel Lasch, Kerstin Troidl, Thomas Lautz, Amelia Caballero-martinez, Irmengard Schloegl, Elisabeth DeindlAbstract:l -Arginine is the common substrate for nitric oxide synthases (NOS) and arginase. Whereas the contribution of NOS to collateral artery growth (Arteriogenesis) has been demonstrated, the functional role of arginase remains to be elucidated and was topic of the present study. Arteriogenesis was induced in mice by ligation of the femoral artery. Laser Doppler perfusion measurements demonstrated a significant reduction in Arteriogenesis in mice treated with the arginase inhibitor nor-NOHA (N^ω-hydroxy-nor-arginine). Accompanying in vitro results on murine primary arterial endothelial cells and smooth muscle cells revealed that nor-NOHA treatment interfered with cell proliferation and resulted in increased nitrate/nitrite levels, indicative for increased NO production. Immuno-histological analyses on tissue samples demonstrated that nor-NOHA administration caused a significant reduction in M2 macrophage accumulation around growing collateral arteries. Gene expression studies on isolated growing collaterals evidenced that nor-NOHA treatment abolished the differential expression of Icam 1 (intercellular adhesion molecule 1). From our data we conclude that arginase activity is essential for Arteriogenesis by promoting perivascular M2 macrophage accumulation as well as arterial cell proliferation.
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Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function.
Cell Reports, 2016Co-Authors: Omary Chillo, Silvia Fischer, Kerstin Troidl, Eike Christian Kleinert, Thomas Lautz, Manuel Lasch, Judith-irina Pagel, Yvonn Heun, Amelia Caballero-martinez, Annika MauerAbstract:Summary The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (Arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit + /CXCR-4 + cells stimulate Arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes Arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced Arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases.
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rgs5 promotes arterial growth during Arteriogenesis
Embo Molecular Medicine, 2014Co-Authors: Caroline Arnold, Kerstin Troidl, Anja Feldner, Larissa Pfisterer, Maren Hodebeck, Guillem Genove, Thomas Wieland, Markus Hecker, Thomas KorffAbstract:Arteriogenesis—the growth of collateral arterioles—partially compensates for the progressive occlusion of large conductance arteries as it may occur as a consequence of coronary, cerebral or peripheral artery disease. Despite being clinically highly relevant, mechanisms driving this process remain elusive. In this context, our study revealed that abundance of regulator of G-protein signalling 5 (RGS5) is increased in vascular smooth muscle cells (SMCs) of remodelling collateral arterioles. RGS5 terminates G-protein-coupled signalling cascades which control contractile responses of SMCs. Consequently, overexpression of RGS5 blunted Gaq/11-mediated mobilization of intracellular calcium, thereby facilitating Ga12/13-mediated RhoA signalling which is crucial for Arteriogenesis. Knockdown of RGS5 evoked opposite effects and thus strongly impaired collateral growth as evidenced by a blockade of RhoA activation, SMC proliferation and the inability of these cells to acquire an activated phenotype in RGS5-deficient mice after the onset of Arteriogenesis. Collectively, these findings establish RGS5 as a novel determinant of Arteriogenesis which shifts G-protein signalling from Gaq/11-mediated calcium-dependent contraction towards Ga12/13-mediated Rho kinase-dependent SMC activation.
Elisabeth Deindl - One of the best experts on this subject based on the ideXlab platform.
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estimating hemodynamic shear stress in murine peripheral collateral arteries by two photon line scanning
Molecular and Cellular Biochemistry, 2019Co-Authors: Manuel Lasch, Judithirina Buchheim, Katharina Nekolla, Anna H Klemm, Ulrich Pohl, Steffen Dietzel, Elisabeth DeindlAbstract:Changes in wall shear stress of blood vessels are assumed to be an important component of many physiological and pathophysiological processes. However, due to technical limitations experimental in vivo data are rarely available. Here, we investigated two-photon excitation fluorescence microscopy as an option to measure vessel diameter as well as blood flow velocities in a murine hindlimb model of Arteriogenesis (collateral artery growth). Using line scanning at high frequencies, we measured the movement of blood cells along the vessel axis. We found that peak systolic blood flow velocity averaged 9 mm/s and vessel diameter 42 µm in resting collaterals. Induction of Arteriogenesis by femoral artery ligation resulted in a significant increase in centerline peak systolic velocity after 1 day with an average of 51 mm/s, whereas the averaged luminal diameter of collaterals (52 µm) changed much less. Thereof calculations revealed a significant fourfold increase in hemodynamic wall shear rate. Our results indicate that two-photon line scanning is a suitable tool to estimate wall shear stress e.g., in experimental animal models, such as of Arteriogenesis, which may not only help to understand the relevance of mechanical forces in vivo, but also to adjust wall shear stress in ex vivo investigations on isolated vessels as well as cell culture experiments.
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midkine controls Arteriogenesis by regulating the bioavailability of vascular endothelial growth factor a and the expression of nitric oxide synthase 1 and 3
EBioMedicine, 2017Co-Authors: Thomas Lautz, Kerstin Troidl, Manuel Lasch, Judith-irina Pagel, Julia Borgolte, Amelia Caballeromartinez, Eike Kleinert, Barbara Walzog, Elisabeth DeindlAbstract:Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in Arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in Arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of Arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.
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Arginase inhibition attenuates Arteriogenesis and interferes with M2 macrophage accumulation
Laboratory Investigation, 2016Co-Authors: Manuel Lasch, Kerstin Troidl, Thomas Lautz, Amelia Caballero-martinez, Irmengard Schloegl, Elisabeth DeindlAbstract:l -Arginine is the common substrate for nitric oxide synthases (NOS) and arginase. Whereas the contribution of NOS to collateral artery growth (Arteriogenesis) has been demonstrated, the functional role of arginase remains to be elucidated and was topic of the present study. Arteriogenesis was induced in mice by ligation of the femoral artery. Laser Doppler perfusion measurements demonstrated a significant reduction in Arteriogenesis in mice treated with the arginase inhibitor nor-NOHA (N^ω-hydroxy-nor-arginine). Accompanying in vitro results on murine primary arterial endothelial cells and smooth muscle cells revealed that nor-NOHA treatment interfered with cell proliferation and resulted in increased nitrate/nitrite levels, indicative for increased NO production. Immuno-histological analyses on tissue samples demonstrated that nor-NOHA administration caused a significant reduction in M2 macrophage accumulation around growing collateral arteries. Gene expression studies on isolated growing collaterals evidenced that nor-NOHA treatment abolished the differential expression of Icam 1 (intercellular adhesion molecule 1). From our data we conclude that arginase activity is essential for Arteriogenesis by promoting perivascular M2 macrophage accumulation as well as arterial cell proliferation.
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the proteoglycan osteoglycin mimecan is correlated with Arteriogenesis
Molecular and Cellular Biochemistry, 2009Co-Authors: Andreas Kampmann, Frederic Pipp, Elisabeth Deindl, Inka Eitenmüller, Wolfgang Schaper, Imo E. Hoefer, Borja Fernandez, Thomas Kubin, Rene ZimmermannAbstract:Arteriogenesis or collateral growth is able to compensate for the stenosis of major arteries. Using differential display RT-PCR on growing and quiescent collateral arteries in a rabbit femoral artery ligation model, we cloned the rabbit full-length cDNA of osteoglycin/mimecan. Osteoglycin was present in the adventitia of collateral arteries as a glycosylated protein without keratan sulfate side chains, mainly produced by smooth muscle cells (SMCs) and perivascular fibroblasts. Northern blot, Western blot, and immunohistochemistry confirmed a collateral artery-specific downregulation of osteoglycin from 6 h to 3 weeks after the onset of Arteriogenesis. Treatment of primary SMCs with the arteriogenic protein fibroblast growth factor-2 (FGF-2) resulted in a similar reduction of osteoglycin expression as observed in vivo. Application of the FGF-2 inhibitor polyanethole sulfonic acid (PAS) blocked the downregulation of osteoglycin and interfered with Arteriogenesis. From our study we conclude that downregulation of osteoglycin is a fundamental requirement for proper Arteriogenesis.
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The art of Arteriogenesis
Cell Biochemistry and Biophysics, 2005Co-Authors: Elisabeth Deindl, Wolfgang SchaperAbstract:The identification of collateral artery growth (Arteriogenesis) as the only mechanism to compensate for the loss of an occluded artery forced us to define the mechanisms responsible for this type of vessel growth. To achieve this, a variety of coronary as well as peripheral models of Arteriogenesis have been developed. Based on these studies it is obvious that Arteriogenesis obeys different mechanisms than angiogenesis, the sprouting of capillaries. Upon occlusion of an artery, the blood flow is redirected into preexisting arteriolar anastomoses that experience increased mechanical forces such as shear stress and circum ferential wall stress. The endothelium of the arteriolar connections is then activated, resulting in an increased release of monocyte-attracting proteins as well as an upregulation of adhesion molecules. Upon adherence and extravasation, monocytes promote Arteriogenesis by supplying growth factors and cytokines that bind to receptors that are expressed on vascular cells within a limited time frame. Animal studies evidenced that factors, such as monocyte chemoattractant protein-1, granulocyte-monocyte colony-stimulating factor, or transforming growth factor-β_1, that either attract or prolong the lifetime of monocytes efficiently enhance collateral artery growth, an effect that was seen only to a minor degree after application of a single growth factor. Bone marrow-derived stems cells and endothelial progenitor cells do not incorporate in growing arteries but, rather, function as supporting cells. Complete elucidation of the mechanisms of Arteriogenesis may lead to efficacious therapies counteracting the devastating consequences of vascular occlusive diseases.
Ivo Buschmann - One of the best experts on this subject based on the ideXlab platform.
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pulsatile shear and gja5 modulate arterial identity and remodeling events during flow driven Arteriogenesis
Development, 2010Co-Authors: Ivo Buschmann, Axel R Pries, Beata Styprekowska, Philipp Hillmeister, Laurent Loufrani, Daniel Henrion, Andre Duelsner, Imo E Hoefer, Nora Gatzke, Haitao WangAbstract:In the developing chicken embryo yolk sac vasculature, the expression of arterial identity genes requires arterial hemodynamic conditions. We hypothesize that arterial flow must provide a unique signal that is relevant for supporting arterial identity gene expression and is absent in veins. We analyzed factors related to flow, pressure and oxygenation in the chicken embryo vitelline vasculature in vivo. The best discrimination between arteries and veins was obtained by calculating the maximal pulsatile increase in shear rate relative to the time-averaged shear rate in the same vessel: the relative pulse slope index (RPSI). RPSI was significantly higher in arteries than veins. Arterial endothelial cells exposed to pulsatile shear in vitro augmented arterial marker expression as compared with exposure to constant shear. The expression of Gja5 correlated with arterial flow patterns: the redistribution of arterial flow provoked by vitelline artery ligation resulted in flow-driven collateral arterial network formation and was associated with increased expression of Gja5. In situ hybridization in normal and ligation embryos confirmed that Gja5 expression is confined to arteries and regulated by flow. In mice, Gja5 (connexin 40) was also expressed in arteries. In the adult, increased flow drives Arteriogenesis and the formation of collateral arterial networks in peripheral occlusive diseases. Genetic ablation of Gja5 function in mice resulted in reduced Arteriogenesis in two occlusion models. We conclude that pulsatile shear patterns may be central for supporting arterial identity, and that arterial Gja5 expression plays a functional role in flow-driven Arteriogenesis.
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anti tumor necrosis factor α therapies attenuate adaptive Arteriogenesis in the rabbit
American Journal of Physiology-heart and Circulatory Physiology, 2005Co-Authors: Sebastian Grundmann, Stephan H Schirmer, Imo E. Hoefer, Jan J Piek, Christoph Bode, Niels Van Royen, Keith C Ozaki, Susann Ulusans, Ivo BuschmannAbstract:The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Because proliferation of arteriolar connections toward functional collateral arteries (Arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept have antiarteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept, or vehicle according to clinical dosage regimes. After 1 wk, collateral conductance, assessed with fluorescent microspheres, revealed significant inhibition of Arteriogenesis (collateral conductance): 52.4 (SD 8.1), 35.2 (SD 7.7), and 33.3 (SD 10.1) ml x min(-1) x 100 mmHg(-1) with PBS, infliximab, and etanercept, respectively (P < 0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, proliferation of vascular smooth muscle cells, and reduction of leukocyte accumulation around collateral arteries in treated groups. Infliximab and etanercept bound to infiltrating leukocytes, which are important mediators of Arteriogenesis. Infliximab induced monocyte apoptosis, and neither substance affected monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF-alpha serves as a pivotal modulator of Arteriogenesis, which is attenuated by treatment with TNF-alpha inhibitors. Reduction of collateral conductance is most likely due to inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF-alpha inhibitors on collateral artery growth.
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divergent effects of gm csf and tgfβ1 on bone marrow derived macrophage arginase 1 activity mcp 1 expression and matrix metalloproteinase 12 a potential role during Arteriogenesis
The FASEB Journal, 2003Co-Authors: Marco Jost, Imo E. Hoefer, Niels Van Royen, Jing Hua, Elena Ninci, Benjamin Meder, Caroline Kempf, Bernhard J Berger, Manuel Modolell, Ivo BuschmannAbstract:Granulocyte/macrophage-colony stimulating factor (GM-CSF) and transforming growth factor (TGF)beta1 induce Arteriogenesis in a nonischemic model of femoral artery ligation. Moreover, clinical trials demonstrated an improved collateralization after injection of bone marrow cells. In the present study, the expression of arteriogenic factors in bone marrow-derived macrophages (BMDM) was measured to verify the potential of these cells to influence collateral artery growth. GM-CSF induced in BMDM the expression of monocyte chemoattractive protein (MCP)-1, matrix-metalloproteinase (MMP)-12, and arginase-1-the latter also showing a remarkable increase in activity. During in vivo induced Arteriogenesis, the accumulation rate of macrophages around proliferating collaterals was significantly increased. We also show that MCP-1 is found to be mainly expressed in the media of the vessel wall, MMP-12 in macrophages of the adventitia, and arginase at both locations. This study provides for the first time a comprehensive analysis of GM-CSF/TGFbeta1-regulated arteriogenic factors in BMDM and supports the hypothesis that Arteriogenesis is a multistage mechanism, including monocyte/macrophage adhesion and transmigration, pro-arteriogenic cytokine expression, degradation of connective tissue, and collagen synthesis regulation. Selective modulation of these mechanisms as well as cell-based therapies supplying arteriogenic factors in vivo point toward new strategies to influence collateral artery growth.
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therapeutic induction of Arteriogenesis in hypoperfused rat brain via granulocyte macrophage colony stimulating factor
Circulation, 2003Co-Authors: Ivo Buschmann, Hansjorg Busch, Gunter Mies, Konstantinalexander HossmannAbstract:Background—Colony-stimulating factors (CSFs) have been shown to effectively induce Arteriogenesis in the hindlimb. Moreover, clinical trials demonstrated positive effects of CSFs on Arteriogenesis in patients with coronary artery disease. However, patients with cerebrovascular disease have not yet profited from treatments aimed at the growth of brain vessels. Thus far, angiogenesis studies have failed to demonstrate improvement of stroke outcome. Arteriogenesis differs from angiogenesis in that it substitutes arterial collaterals for the occluded artery. Methods and Results—We tested in a novel brain Arteriogenesis rat model (occlusion of vertebral plus left carotid artery [3-VO]) the application of CSFs or saline over 7 or 21 days. On 3-VO postmortem, latex perfusion demonstrated a timeand treatment-dependent Arteriogenesis of the posterior cerebral artery (PCA). In saline-treated animals, the PCA diameter increased by 39%; in granulocyte-macrophage (GM)-CSF-treated animals, this increase was significantly faster (72% after 1 week). Functionally, saline-treated animals exhibited a decline of CO 2 reactivity (mm Hg) from 1.48% to 0.1% compared with GM-CSF–treated animals (1.43% arterial pCO2 change after 1 week). This difference remained significant after 3 weeks. This functional improvement correlated with increased numbers of CD68-positive macrophages in histological sections of the PCA in GM-CSF–treated animals and only a few macrophages in saline-treated animals. Conclusions—To the best of our knowledge, this is the first report of stimulation of Arteriogenesis in the brain. The subcutaneous application of GM-CSF led to functional improvement of brain hemodynamic parameters. (Circulation. 2003;108:610-615.)
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influence of inflammatory cytokines on Arteriogenesis
Microcirculation, 2003Co-Authors: Ivo Buschmann, Matthias Heil, Marco Jost, Wolfgang SchaperAbstract:Blood vessel growth after birth is limited to two major processes. Angiogenesis is the growth of new capillaries by sprouting or intussusception. The major stimulus for angiogenesis is ischemia. In contrast, Arteriogenesis describes the remodeling and growth of collateral arteries from a preexisting arteriolar network. Arteriogenesis is induced after the occlusion of a major artery which induces hemodynamic and mechanical effects on the collateral vessel wall which occur with increasing blood flow velocity due to the low pressure at the reentrant site of the collateral vessel. A variety of different cytokines that act by stimulating endothelial and smooth muscle cell proliferation and migration or recruitment and activation of monocytes have been identified to stimulate angiogenesis and/or Arteriogenesis (i.e., MCP-1, FGF-2, TGF-beta, VEGF, and GM-CSF). Several clinical trials have been published in that field to suggest the feasibility and safety of treatment with such cytokines or their genes. However, the results indicate that further studies are needed before proangiogenic and proarteriogenic therapies are ready for clinical application.
Imo E. Hoefer - One of the best experts on this subject based on the ideXlab platform.
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microrna 132 212 family enhances Arteriogenesis after hindlimb ischaemia through modulation of the ras mapk pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Zhiyong Lei, Imo E. Hoefer, Sebastian Grundmann, Alain Van Mil, Maarten M Brandt, Michiel Smits, Hamid El Azzouzi, Taro Fukao, Caroline ChengAbstract:Arteriogenesis is a complicated process induced by increased local shear-and radial wall-stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of Arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR-132/212 expression was significantly upregulated after occlusion of the femoral artery. miR-132/212 knockout (KO) mice display a slower perfusion recovery after hind-limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR-132/212 KO mice compared to WT, it can be stimulated with exogenous miR-132, a dominant member of the miR-132/212 family. Moreover, in in vitro pericyte-endothelial co-culture cell assays, overexpression of miR-132 and mir-212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR-132/212 may exert their effects by enhancing the Ras-Mitogen-activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR-132/212 cluster promotes Arteriogenesis by modulating Ras-MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1.
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the cd200 cd200 receptor inhibitory axis controls Arteriogenesis and local t lymphocyte influx
PLOS ONE, 2014Co-Authors: Pleunie Van Den Borne, Imo E. Hoefer, Tomasz P. Rygiel, Ayla Hoogendoorn, Geertje H A Westerlaken, Louis Boon, Paul H A Quax, Gerard Pasterkamp, Linde MeyaardAbstract:The role of the CD200 ligand-CD200 receptor (CD200-CD200R) inhibitory axis is highly important in controlling myeloid cell function. Since the activation of myeloid cells is crucial in Arteriogenesis, we hypothesized that disruption of the CD200-CD200R axis promotes Arteriogenesis in a murine hindlimb ischemia model. Female Cd200−/− and wildtype (C57Bl/6J) mice underwent unilateral femoral artery ligation. Perfusion recovery was monitored over 7 days using Laser-Doppler analysis and was increased in Cd200−/− mice at day 3 and 7 after femoral artery ligation, compared to wildtype. Histology was performed on hindlimb muscles at baseline, day 3 and 7 to assess vessel geometry and number and inflammatory cell influx. Vessel geometry in non-ischemic muscles was larger, and vessel numbers in ischemic muscles were increased in Cd200−/− mice compared to wildtype. Furthermore, T lymphocyte influx was increased in Cd200−/− compared to wildtype. CD200R agonist treatment was performed in male C57Bl/6J mice to validate the role of the CD200-CD200R axis in Arteriogenesis. CD200R agonist treatment after unilateral femoral artery ligation resulted in a significant decrease in vessel geometry, perfusion recovery and T lymphocyte influx at day 7 compared to isotype treatment. In this study, we show a causal role for the CD200-CD200R inhibitory axis in Arteriogenesis in a murine hindlimb ischemia model. Lack of CD200R signaling is accompanied by increased T lymphocyte recruitment to the collateral vasculature and results in enlargement of preexisting collateral arteries.
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the proteoglycan osteoglycin mimecan is correlated with Arteriogenesis
Molecular and Cellular Biochemistry, 2009Co-Authors: Andreas Kampmann, Frederic Pipp, Elisabeth Deindl, Inka Eitenmüller, Wolfgang Schaper, Imo E. Hoefer, Borja Fernandez, Thomas Kubin, Rene ZimmermannAbstract:Arteriogenesis or collateral growth is able to compensate for the stenosis of major arteries. Using differential display RT-PCR on growing and quiescent collateral arteries in a rabbit femoral artery ligation model, we cloned the rabbit full-length cDNA of osteoglycin/mimecan. Osteoglycin was present in the adventitia of collateral arteries as a glycosylated protein without keratan sulfate side chains, mainly produced by smooth muscle cells (SMCs) and perivascular fibroblasts. Northern blot, Western blot, and immunohistochemistry confirmed a collateral artery-specific downregulation of osteoglycin from 6 h to 3 weeks after the onset of Arteriogenesis. Treatment of primary SMCs with the arteriogenic protein fibroblast growth factor-2 (FGF-2) resulted in a similar reduction of osteoglycin expression as observed in vivo. Application of the FGF-2 inhibitor polyanethole sulfonic acid (PAS) blocked the downregulation of osteoglycin and interfered with Arteriogenesis. From our study we conclude that downregulation of osteoglycin is a fundamental requirement for proper Arteriogenesis.
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interferon β signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits Arteriogenesis in mice
Circulation Research, 2008Co-Authors: Stephan H Schirmer, Perry D. Moerland, Anton J G Horrevoets, Imo E. Hoefer, Jan J Piek, René J. Van Der Schaaf, José P.s. Henriques, Joost O. Fledderus, Jan Baan, Niels Van RoyenAbstract:Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as Arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate Arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, >0.21) and nonresponders (collateral flow index, ≤0.21). Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during Arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P , P
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interferon beta signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits Arteriogenesis in mice
Circulation Research, 2008Co-Authors: Stephan H Schirmer, Perry D. Moerland, Imo E. Hoefer, José P.s. Henriques, Joost O. Fledderus, Jan Baan, Pieter T Bot, Rene J Van Der Schaaf, Marije M Vis, Anton J G HorrevoetsAbstract:Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as Arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate Arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, >0.21) and nonresponders (collateral flow index, < or 1). Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during Arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P, <0.05) in stimulated monocytes. Interferon (IFN)-beta and several IFN-related genes showed increased mRNA levels in 3 of 4 cellular phenotypes from nonresponders. Macrophage gene expression correlated with stimulated monocytes, whereas resting monocytes and progenitor cells did not display differential gene regulation. In vitro, IFN-beta dose-dependently inhibited smooth muscle cell proliferation. In a murine hindlimb model, perfusion measured 7 days after femoral artery ligation showed attenuated Arteriogenesis in IFN-beta-treated mice compared with controls (treatment versus control: 31.5+/-1.2% versus 41.9+/-1.9% perfusion restoration, P<0.01). In conclusion, patients with differing arteriogenic response as measured with collateral flow index display differential transcriptomes of stimulated monocytes. Nonresponders show increased expression of IFN-beta and its downstream targets, and IFN-beta attenuates proliferation of smooth muscle cells in vitro and hampers Arteriogenesis in mice. Inhibition of IFN-beta signaling may serve as a novel approach for the stimulation of collateral artery growth.