- Email: [email protected]
Endothelial Von Willebrand factor regulates angiogenesis
318
Abstracts
SESSION 5 Microvesicles, cell communication and vascular homeostasis L.5.1 The multifaceted role of endothelial derived microparticles Françoise Dignat-George INSERM-UMR-608, Laboratoire Hématologie et Immunologie, UFR de Pharmacie, Université de la Méditerranée, Marseille, France E-mail address: [email protected] Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They express a large repertoire of endothelial molecules and biological functions that are related to their potential involvement in the tuning of vascular homeostasis. Indeed, they play a pivotal role in coagulation, inflammation, endothelial function and angiogenesis and thus, disturb the vascular equilibrium, contributing to the progression of vascular diseases. As a cause and/or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial alterations. More recent data challenged the presumed deleterious role of EMP since they could promote cell survival, exert anti-inflammatory effects, counteract coagulation processes or induce endothelial generation. In the future, elucidating the multifaceted role of EMP in vascular homeostasis and their mechanisms of formation will bring new insights into the understanding of endothelial-associated diseases and could open novel pharmacological approaches manipulating EMP generation. doi:10.1016/j.vph.2011.08.035
L.5.2 Microparticles, vascular function and atherothrombosis Chantal M. Boulanger, Pierre-Emmanuel Rautou, Anne-Clémence Vion, Nicolas Amabile, Gilles Chironi, Alain Simon, Alain Tedgui INSERM, U970, Paris Cardiovascular Research Center PARCC, Paris, France and Université Paris Descartes, UMR-S970, Paris, France E-mail address: [email protected] (C. M. Boulanger) Membrane-shed submicron microparticles (MPs) are released following cell activation or apoptosis. High levels of MPs circulate in the blood of patients with atherothrombotic diseases, where they could serve as a useful biomarker of vascular injury and a potential predictor of cardiovascular mortality and major adverse cardiovascular events. Atherosclerotic lesions also accumulate large numbers of MPs of leukocyte, smooth muscle cell, endothelial and erythrocyte origin. A large body of evidence supports the role of MPs at different steps of atherosclerosis development, progression and complications. Circulating MPs impair the atheroprotective function of the vascular endothelium, at least partly by decreased nitric oxide synthesis. Plaque MPs also favor local inflammation by augmenting the expression of adhesion molecule such as ICAM-1 at the surface of endothelial cell, and monocyte recruitment within the lesion. In addition, plaque MPs stimulate angiogenesis, a key event in the transition from stable to unstable lesions. MPs may also promote local cell apoptosis, leading to the release and accumulation of new MPs, and thus creating a vicious circle. Furthermore, highly thrombogenic plaque MPs could increase thrombus formation at the time of rupture, together with circulating MPs released in this context by activated platelets and leukocytes. Finally, MPs could also participate in repairing the consequences of arterial occlusion and tissue ischemia by promoting post-ischemic neovascularization. doi:10.1016/j.vph.2011.08.036
L.5.3 Microparticles as transfer modules in cardiovascular disease Christian Weber Institute for Cardiovascular Prevention, Ludiwg-Maximilians-University, Munich, Germany E-mail address: [email protected] Microparticles represent a heterogeneous population of vesicles with a diameter of 100 to 1000 nm that are released by budding of the plasma membrane and express antigens specific of their parental cells. Although microparticle formation represents a physiological phenomenon, a multitude of pathologies are associated with a considerable increase in circulating microparticles, including inflammatory and autoimmune diseases, atherosclerosis, and malignancies. Microparticles display a broad spectrum of bioactive substances and receptors on their surface and harbor a concentrated set of cytokines, signaling proteins, mRNA, and microRNA. Recent studies provided evidence for the concept of microparticles as veritable vectors for the intercellular exchange of biological signals and information. Indeed, microparticles may transfer part of their components and content, e.g. chemokine receptors, to selected target cells, thus mediating cell activation, phenotypic modification, and reprogramming of cell function. Because microparticles readily circulate in the vasculature, they may serve as shuttle modules and signaling transducers not only in their local environment but also at remarkable distance from their site of origin. Altogether, this transcellular delivery system may extend the confines of the limited transcriptome and proteome of recipient cells and establishes a communication network in which specific properties and information among cells can be efficiently shared. The sequential steps of the transfer process underlie complex regulatory mechanisms, including selective packaging of microparticle components, specificity of interactions with target cells determined by surface receptors and finely tuned and signal-dependent delivery of microparticle content.
doi:10.1016/j.vph.2011.08.037
O.5.1 Endothelial Von Willebrand factor regulates angiogenesis Richard D. Starkea, Koralia E. Paschalakic, Francesco Ferrarob, Nicola H. Drydena, Thomas A.J. McKinnond, Rachel E. Suttona, Elspeth M. Paynea, Dorian O. Haskarda, Alun D. Hughese, Daniel F. Cutlerb, Mike A. Laffand, Anna M. Randia a Cardiovascular Sciences, NHLI, Imperial College, London, UK b MRC Laboratory of Molecular Cell Biology, University College, London, UK c Airway Disease Department, NHLI, Imperial College, London, UK d Department of Haematology, Imperial College, London, UK e International Centre for Circulatory Health, NHLI, Imperial College & Imperial College Healthcare NHS Trust, London, UK E-mail address: [email protected] (A. M. Randi) Dysregulation of angiogenesis is implicated in many diseases. Von Willebrand factor (VWF), a large plasma glycoprotein essential for normal haemostasis is synthesised by endothelial cells (EC) and megakaryocytes. Raised VWF plasma levels are a risk factor for arterial thrombosis, whilst deficiency of VWF causes Von Willebrand disease (VWD), the most common congenital bleeding disorder in man. VWD can be associated with angiodysplasia, vascular malformations linked to defective angiogenesis which are responsible for intractable gastrointestinal bleeding. We hypothesised that VWF is involved in angiogenesis. To test this hypothesis, we isolated mononuclear cells from peripheral blood of controls and patients with VWD and cultured them to obtain confluent monolayers of blood outgrowth endothelial cells
Abstracts
(BOEC). BOEC from VWD patients showed decreased VWF release, consistent with the patients' clinical data, increased capillary tube formation on Matrigel, migration and proliferation compared to controls. Thus BOEC from VWD patients exhibit enhanced angiogenic properties. Increased angiogenesis was also observed after inhibition of VWF expression in human umbilical vein EC (HUVEC) with specific siRNA. Mechanism studies on VWF siRNA-treated HUVEC implicated the endothelial VWF receptor, integrin alphavbeta3 and the angiogenesis regulator angiopoietin-2. To validate our findings in an in vivo model we studied the VWF-deficient mouse. In vivo Matrigel angiogenesis and imaging of blood vessels in the ear showed increased angiogenesis and vascular network compared to littermate controls. Thus we have identified a novel mechanism for the regulation of angiogenesis and a new function for VWF, which may have clinical implications for VWD and for CV disease. doi:10.1016/j.vph.2011.08.038
O.5.2 Low shear stress release procoagulant endothelial microparticles by a RhoK and ERK1/2-MAPK-dependent mechanism Anne-Clémence Vion, Bhama Ramkhelawon, Alain Tedgui, Stéphanie Lehoux, Chantal M. Boulanger INSERM, U970, Paris Cardiovascular Research Center - PARCC, and Université Paris Descartes, Paris, France E-mail addresses: [email protected] (A.-C. Vion), [email protected] (C. M. Boulanger) Endothelial microparticles (EMP) are shed-membrane sub-micron vesicles released upon cell activation or apoptosis. EMP plasma levels are surrogate markers of endothelial dysfunction and increase in patients with cardiovascular diseases, but no information on the mechanisms triggering their in vivo release is available. As laminar shear stress (SS) is a major physiological regulator of endothelial survival, we tested the hypothesis that different shear stress levels may affect EMP release. Confluent HUVECs (passage 1–3) were subjected to high, low SS or static conditions for 24 h (15, 1.5 and 0 dyne/cm2, respectively). AnnexinV+ EMPs were analyzed by flow cytometry of cell culture medium and signaling pathways were identified by Western Blot analysis. HUVECs exposed to high SS released 3-fold less MPs compared to static and low SS conditions (static: 384 ± 31, Low SS: 326 ± 37, high SS: 130 ± 23AnnV + MPs/μL, p < 0.001). As static conditions and low SS promote cell apoptosis, we investigated whether or not endothelial apoptosis mediated EMP shedding. Exposure to Z-VAD-FMK (20 nM; a pan-caspase inhibitor), decreased EMP shedding by 63 ± 7% under static conditions (p < 0.001) corroborating Tunel assay data, but surprisingly did not affect EMP release upon low SS (p = 0.94). EMP release upon low SS conditions was impaired following inhibition of ERK1/2 (by 52 ± 10%, p < 0.01) and ROCK pathways (by 63 ± 8%, p < 0.05), but unaffected by inhibitors of p38 MAPK or NFκB pathways, which are involved in TNFα-induced EMP release. Low SS increased ERK1/2 phosphorylation by 2-fold (p < 0.05) and this was inhibited by 77 ± 8% following ROCK inhibition by Y27632 (p < 0.05). The inhibitory effect of high SS on EMP release was likely to be mediated by NO release as L-NAME (10− 5 M) increased high SS-induced EMPs levels by 3.2-fold (p < 0.001) and the NO donor SNAP (10− 5 M) significantly decreased low SS-induced EMP release by 50 ± 16% (p = 0.05). Altogether, these results demonstrate that low SS releases procoagulant EMPs via the activation of ROCK and ERK1/2 pathways, whereas high SS limits EMP release by a NO-dependent pathway. These findings therefore identify endothelial shear stress as a physiological regulator of endothelial microparticle release. doi:10.1016/j.vph.2011.08.039
319
O.5.3 Matrix metalloproteinase-10: A product of classically-activated plaque macrophages with a putative role in collagenolysis Graciela B. Sala-Newby, Wei-Chun Huang, Jason L. Johnson, Andrew C. Newby Bristol Heart Institute, Bristol University, BS2 8HW, Bristol, UK E-mail address: [email protected] (G. B. Sala-Newby) Matrix metalloproteinases (MMPs) participate in atherogenesis by modulating migration, proliferation and apoptosis of vascular cells. Excessive degradation of extracellular matrix by MMPs is believed to underlie atherosclerotic plaque rupture and therefore myocardial infarction. There are 24 MMPs that collectively can degrade all extracellular matrix components and many non-matrix substrates, including the pro-forms of other MMPs. The regulation of MMP-10, a stromelysin with broad specificity including pro-MMP-1, has received relatively little attention. We therefore used quantitative PCR, western blotting and immunohistochemistry to study its production from human macrophages, and macrophage-derived foam cells in vitro and in human coronary plaques from cadaveric donors. Data are expressed as mean (95% confidence interval) or mean ± SD if normally distributed. Expression of MMP-10 mRNA increased 12(5–10) fold during classical macrophage activation with bacterial lipolysaccharide and IFN-γ but was unchanged during alternative activation with IL-4. Messenger RNAs for COX-2, a marker for classical activation, and proMMP-1, a putative substrate of MMP-10, increased 114(68–192) fold, and 10(5–20) fold in classically-activated macrophages (n = 7). Similar results were obtained with foam-cells generated by oxidised-LDL treatment in vitro. MMP-10 mRNA increased 89, 11, 14 fold with LPS, TNFα, and IL-1α but not significantly with IFN-γ alone (n = 4). Consistent with the mRNA data, MMP-10 and COX-2 proteins were detectable by western blotting in classically-activated but not in control or alternatively-activated macrophages. Studies into the mechanisms involved implicated activation of c-jun-N-terminal kinase and NF-κB in MMP-10, COX-2 and MMP-1 mRNA and protein expression (results not shown). Co-localisation of MMP-10 with COX2 and MMP-1 was examined in CD68-positive plaque macrophages (see the Table). Percentage ± SD (n = 6)
+/+
+/−
−/+
−/−
MMP-10, COX-2 MMP-10, MMP-1 MMP-1, COX-2
59 ± 10 61 ± 9 57 ± 8
11 ± 6 9±6 13 ± 10
10 ± 6 8±7 7±7
21 ± 7 22 ± 9 22 ± 6
In conclusion, MMP-10 was co-regulated in vitro and co-localised in vivo with COX-2 and pro-MMP-1. MMP-10 produced in response to classical macrophage activation could therefore participate in a proteolytic cascade leading to collagenolysis, weakening of the plaque fibrous cap and hence rupture. doi:10.1016/j.vph.2011.08.040
SESSION 6 Hypoxia and other vascular signalling L.6.1 NADPH oxidases and the HIF pathway: An emerging liaison in vascular cells Agnes Görlach Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the TU Munich, Lazarettstr 36, D-80636 Munich, Germany E-mail address: [email protected]
Abstracts
SESSION 5 Microvesicles, cell communication and vascular homeostasis L.5.1 The multifaceted role of endothelial derived microparticles Françoise Dignat-George INSERM-UMR-608, Laboratoire Hématologie et Immunologie, UFR de Pharmacie, Université de la Méditerranée, Marseille, France E-mail address: [email protected] Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They express a large repertoire of endothelial molecules and biological functions that are related to their potential involvement in the tuning of vascular homeostasis. Indeed, they play a pivotal role in coagulation, inflammation, endothelial function and angiogenesis and thus, disturb the vascular equilibrium, contributing to the progression of vascular diseases. As a cause and/or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial alterations. More recent data challenged the presumed deleterious role of EMP since they could promote cell survival, exert anti-inflammatory effects, counteract coagulation processes or induce endothelial generation. In the future, elucidating the multifaceted role of EMP in vascular homeostasis and their mechanisms of formation will bring new insights into the understanding of endothelial-associated diseases and could open novel pharmacological approaches manipulating EMP generation. doi:10.1016/j.vph.2011.08.035
L.5.2 Microparticles, vascular function and atherothrombosis Chantal M. Boulanger, Pierre-Emmanuel Rautou, Anne-Clémence Vion, Nicolas Amabile, Gilles Chironi, Alain Simon, Alain Tedgui INSERM, U970, Paris Cardiovascular Research Center PARCC, Paris, France and Université Paris Descartes, UMR-S970, Paris, France E-mail address: [email protected] (C. M. Boulanger) Membrane-shed submicron microparticles (MPs) are released following cell activation or apoptosis. High levels of MPs circulate in the blood of patients with atherothrombotic diseases, where they could serve as a useful biomarker of vascular injury and a potential predictor of cardiovascular mortality and major adverse cardiovascular events. Atherosclerotic lesions also accumulate large numbers of MPs of leukocyte, smooth muscle cell, endothelial and erythrocyte origin. A large body of evidence supports the role of MPs at different steps of atherosclerosis development, progression and complications. Circulating MPs impair the atheroprotective function of the vascular endothelium, at least partly by decreased nitric oxide synthesis. Plaque MPs also favor local inflammation by augmenting the expression of adhesion molecule such as ICAM-1 at the surface of endothelial cell, and monocyte recruitment within the lesion. In addition, plaque MPs stimulate angiogenesis, a key event in the transition from stable to unstable lesions. MPs may also promote local cell apoptosis, leading to the release and accumulation of new MPs, and thus creating a vicious circle. Furthermore, highly thrombogenic plaque MPs could increase thrombus formation at the time of rupture, together with circulating MPs released in this context by activated platelets and leukocytes. Finally, MPs could also participate in repairing the consequences of arterial occlusion and tissue ischemia by promoting post-ischemic neovascularization. doi:10.1016/j.vph.2011.08.036
L.5.3 Microparticles as transfer modules in cardiovascular disease Christian Weber Institute for Cardiovascular Prevention, Ludiwg-Maximilians-University, Munich, Germany E-mail address: [email protected] Microparticles represent a heterogeneous population of vesicles with a diameter of 100 to 1000 nm that are released by budding of the plasma membrane and express antigens specific of their parental cells. Although microparticle formation represents a physiological phenomenon, a multitude of pathologies are associated with a considerable increase in circulating microparticles, including inflammatory and autoimmune diseases, atherosclerosis, and malignancies. Microparticles display a broad spectrum of bioactive substances and receptors on their surface and harbor a concentrated set of cytokines, signaling proteins, mRNA, and microRNA. Recent studies provided evidence for the concept of microparticles as veritable vectors for the intercellular exchange of biological signals and information. Indeed, microparticles may transfer part of their components and content, e.g. chemokine receptors, to selected target cells, thus mediating cell activation, phenotypic modification, and reprogramming of cell function. Because microparticles readily circulate in the vasculature, they may serve as shuttle modules and signaling transducers not only in their local environment but also at remarkable distance from their site of origin. Altogether, this transcellular delivery system may extend the confines of the limited transcriptome and proteome of recipient cells and establishes a communication network in which specific properties and information among cells can be efficiently shared. The sequential steps of the transfer process underlie complex regulatory mechanisms, including selective packaging of microparticle components, specificity of interactions with target cells determined by surface receptors and finely tuned and signal-dependent delivery of microparticle content.
doi:10.1016/j.vph.2011.08.037
O.5.1 Endothelial Von Willebrand factor regulates angiogenesis Richard D. Starkea, Koralia E. Paschalakic, Francesco Ferrarob, Nicola H. Drydena, Thomas A.J. McKinnond, Rachel E. Suttona, Elspeth M. Paynea, Dorian O. Haskarda, Alun D. Hughese, Daniel F. Cutlerb, Mike A. Laffand, Anna M. Randia a Cardiovascular Sciences, NHLI, Imperial College, London, UK b MRC Laboratory of Molecular Cell Biology, University College, London, UK c Airway Disease Department, NHLI, Imperial College, London, UK d Department of Haematology, Imperial College, London, UK e International Centre for Circulatory Health, NHLI, Imperial College & Imperial College Healthcare NHS Trust, London, UK E-mail address: [email protected] (A. M. Randi) Dysregulation of angiogenesis is implicated in many diseases. Von Willebrand factor (VWF), a large plasma glycoprotein essential for normal haemostasis is synthesised by endothelial cells (EC) and megakaryocytes. Raised VWF plasma levels are a risk factor for arterial thrombosis, whilst deficiency of VWF causes Von Willebrand disease (VWD), the most common congenital bleeding disorder in man. VWD can be associated with angiodysplasia, vascular malformations linked to defective angiogenesis which are responsible for intractable gastrointestinal bleeding. We hypothesised that VWF is involved in angiogenesis. To test this hypothesis, we isolated mononuclear cells from peripheral blood of controls and patients with VWD and cultured them to obtain confluent monolayers of blood outgrowth endothelial cells
Abstracts
(BOEC). BOEC from VWD patients showed decreased VWF release, consistent with the patients' clinical data, increased capillary tube formation on Matrigel, migration and proliferation compared to controls. Thus BOEC from VWD patients exhibit enhanced angiogenic properties. Increased angiogenesis was also observed after inhibition of VWF expression in human umbilical vein EC (HUVEC) with specific siRNA. Mechanism studies on VWF siRNA-treated HUVEC implicated the endothelial VWF receptor, integrin alphavbeta3 and the angiogenesis regulator angiopoietin-2. To validate our findings in an in vivo model we studied the VWF-deficient mouse. In vivo Matrigel angiogenesis and imaging of blood vessels in the ear showed increased angiogenesis and vascular network compared to littermate controls. Thus we have identified a novel mechanism for the regulation of angiogenesis and a new function for VWF, which may have clinical implications for VWD and for CV disease. doi:10.1016/j.vph.2011.08.038
O.5.2 Low shear stress release procoagulant endothelial microparticles by a RhoK and ERK1/2-MAPK-dependent mechanism Anne-Clémence Vion, Bhama Ramkhelawon, Alain Tedgui, Stéphanie Lehoux, Chantal M. Boulanger INSERM, U970, Paris Cardiovascular Research Center - PARCC, and Université Paris Descartes, Paris, France E-mail addresses: [email protected] (A.-C. Vion), [email protected] (C. M. Boulanger) Endothelial microparticles (EMP) are shed-membrane sub-micron vesicles released upon cell activation or apoptosis. EMP plasma levels are surrogate markers of endothelial dysfunction and increase in patients with cardiovascular diseases, but no information on the mechanisms triggering their in vivo release is available. As laminar shear stress (SS) is a major physiological regulator of endothelial survival, we tested the hypothesis that different shear stress levels may affect EMP release. Confluent HUVECs (passage 1–3) were subjected to high, low SS or static conditions for 24 h (15, 1.5 and 0 dyne/cm2, respectively). AnnexinV+ EMPs were analyzed by flow cytometry of cell culture medium and signaling pathways were identified by Western Blot analysis. HUVECs exposed to high SS released 3-fold less MPs compared to static and low SS conditions (static: 384 ± 31, Low SS: 326 ± 37, high SS: 130 ± 23AnnV + MPs/μL, p < 0.001). As static conditions and low SS promote cell apoptosis, we investigated whether or not endothelial apoptosis mediated EMP shedding. Exposure to Z-VAD-FMK (20 nM; a pan-caspase inhibitor), decreased EMP shedding by 63 ± 7% under static conditions (p < 0.001) corroborating Tunel assay data, but surprisingly did not affect EMP release upon low SS (p = 0.94). EMP release upon low SS conditions was impaired following inhibition of ERK1/2 (by 52 ± 10%, p < 0.01) and ROCK pathways (by 63 ± 8%, p < 0.05), but unaffected by inhibitors of p38 MAPK or NFκB pathways, which are involved in TNFα-induced EMP release. Low SS increased ERK1/2 phosphorylation by 2-fold (p < 0.05) and this was inhibited by 77 ± 8% following ROCK inhibition by Y27632 (p < 0.05). The inhibitory effect of high SS on EMP release was likely to be mediated by NO release as L-NAME (10− 5 M) increased high SS-induced EMPs levels by 3.2-fold (p < 0.001) and the NO donor SNAP (10− 5 M) significantly decreased low SS-induced EMP release by 50 ± 16% (p = 0.05). Altogether, these results demonstrate that low SS releases procoagulant EMPs via the activation of ROCK and ERK1/2 pathways, whereas high SS limits EMP release by a NO-dependent pathway. These findings therefore identify endothelial shear stress as a physiological regulator of endothelial microparticle release. doi:10.1016/j.vph.2011.08.039
319
O.5.3 Matrix metalloproteinase-10: A product of classically-activated plaque macrophages with a putative role in collagenolysis Graciela B. Sala-Newby, Wei-Chun Huang, Jason L. Johnson, Andrew C. Newby Bristol Heart Institute, Bristol University, BS2 8HW, Bristol, UK E-mail address: [email protected] (G. B. Sala-Newby) Matrix metalloproteinases (MMPs) participate in atherogenesis by modulating migration, proliferation and apoptosis of vascular cells. Excessive degradation of extracellular matrix by MMPs is believed to underlie atherosclerotic plaque rupture and therefore myocardial infarction. There are 24 MMPs that collectively can degrade all extracellular matrix components and many non-matrix substrates, including the pro-forms of other MMPs. The regulation of MMP-10, a stromelysin with broad specificity including pro-MMP-1, has received relatively little attention. We therefore used quantitative PCR, western blotting and immunohistochemistry to study its production from human macrophages, and macrophage-derived foam cells in vitro and in human coronary plaques from cadaveric donors. Data are expressed as mean (95% confidence interval) or mean ± SD if normally distributed. Expression of MMP-10 mRNA increased 12(5–10) fold during classical macrophage activation with bacterial lipolysaccharide and IFN-γ but was unchanged during alternative activation with IL-4. Messenger RNAs for COX-2, a marker for classical activation, and proMMP-1, a putative substrate of MMP-10, increased 114(68–192) fold, and 10(5–20) fold in classically-activated macrophages (n = 7). Similar results were obtained with foam-cells generated by oxidised-LDL treatment in vitro. MMP-10 mRNA increased 89, 11, 14 fold with LPS, TNFα, and IL-1α but not significantly with IFN-γ alone (n = 4). Consistent with the mRNA data, MMP-10 and COX-2 proteins were detectable by western blotting in classically-activated but not in control or alternatively-activated macrophages. Studies into the mechanisms involved implicated activation of c-jun-N-terminal kinase and NF-κB in MMP-10, COX-2 and MMP-1 mRNA and protein expression (results not shown). Co-localisation of MMP-10 with COX2 and MMP-1 was examined in CD68-positive plaque macrophages (see the Table). Percentage ± SD (n = 6)
+/+
+/−
−/+
−/−
MMP-10, COX-2 MMP-10, MMP-1 MMP-1, COX-2
59 ± 10 61 ± 9 57 ± 8
11 ± 6 9±6 13 ± 10
10 ± 6 8±7 7±7
21 ± 7 22 ± 9 22 ± 6
In conclusion, MMP-10 was co-regulated in vitro and co-localised in vivo with COX-2 and pro-MMP-1. MMP-10 produced in response to classical macrophage activation could therefore participate in a proteolytic cascade leading to collagenolysis, weakening of the plaque fibrous cap and hence rupture. doi:10.1016/j.vph.2011.08.040
SESSION 6 Hypoxia and other vascular signalling L.6.1 NADPH oxidases and the HIF pathway: An emerging liaison in vascular cells Agnes Görlach Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the TU Munich, Lazarettstr 36, D-80636 Munich, Germany E-mail address: [email protected]