Chronic hypoxia aggravates monocrotaline-induced pulmonary arterial hypertension: a rodent relevant model to the human severe form of the disease

International audienc

Macrophage skewing by Phd2 haplodeficiency prevents ischemia by inducing arteriogenesis

The authors are thankful to Dr. P. Carmeliet for scientific discussion and support. VE-Cadherin:CreERT and PDGFRB:Cre transgenic mice were generated at the Cancer Research UK (London, UK) and kindly donated by Dr. R. Adams. The IKKβ floxed mice are a generous gift of Dr. M. Karin (UCSD, La Jolla, CA). The hydroxylase-deficient PHD2 construct was given by Dr. P. Ratcliffe (Oxford, UK).PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.This work was supported by grants from FWO (G.0726.10), Belgium, and from VIB. ED was granted by ARC, SC by FCT, RLO and VF by FWO, AH by DFG. CR was supported by COST action TD0901. MDP was supported by an ERC starting grant

Apport de l'Imagerie par Résonance Magnétique dans l'étude des mécanismes de structuration des matériaux cimentaires : application au suivi des modifications engendrées par le séchage

The aim of the work is to study microstructural evolution of cementitious materials during hydration process and to analyse modifications due to drying effect. Two durability parameters are studied: water content and porosity. An original way for the investigation is to use Magnetic Resonance Imaging MRI. First, we present a bibliographic synthesis for cementitious materials and for MRI applied on porous media to analyse proton density linked to water content and relaxation NMR which gives information of pore size distribution. Then, results obtained with relaxation and MRI, are compared and identified with common destructive methods commonly used in civil engineering. Finally we analyze two important phenomena on cementitious materials: hydration process and hydration coupled to drying.L'objectif de ce travail est d'étudier les évolutions microstructurales des matériaux cimentaires au cours de l'hydratation et d'analyser les dégradations physico-chimiques de ces matériaux lorsqu'ils sont soumis au séchage. Ces évolutions sont caractérisées par les mesures de teneur en eau et de porosité qui sont des paramètres clés pour l'évaluation de la durabilité des matériaux. L'originalité du travail réside en l'utilisation de l'Imagerie par Résonance magnétique IRM. Nous présentons une synthèse bibliographique sur les matériaux cimentaires et sur l'IRM qui permet d'accéder à la densité protonique caractéristique de la teneur en eau et aux temps de relaxation qui donnent une information sur la distribution poreuse. Les résultats sont ensuite identifiés aux données obtenues par des techniques expérimentales du génie civil. Enfin deux problématiques inhérentes aux matériaux cimentaires qui sont l'analyse de l'hydratation et le couplage hydratation/séchage sont étudiées

Apport de l Imagerie par Résonance Magnétique dans l étude des mécanismes de structuration des matériaux cimentaires (application au suivi des modifications engendrées par le séchage)

L objectif de ce travail est d étudier les évolutions microstructurales des matériaux cimentaires au cours de l hydratation et d analyser les dégradations physico-chimiques de ces matériaux lorsqu ils sont soumis au séchage. Ces évolutions sont caractérisées par les mesures de teneur en eau et de porosité qui sont des paramètres clés pour l évaluation de la durabilité des matériaux. L originalité du travail réside en l utilisation de l Imagerie par Résonance magnétique IRM. Nous présentons une synthèse bibliographique sur les matériaux cimentaires et sur l IRM qui permet d accéder à la densité protonique caractéristique de la teneur en eau et aux temps de relaxation qui donnent une information sur la distribution poreuse. Les résultats sont ensuite identifiés aux données obtenues par des techniques expérimentales du génie civil. Enfin deux problématiques inhérentes aux matériaux cimentaires qui sont l analyse de l hydratation et le couplage hydratation/séchage sont étudiéesThe aim of the work is to study microstructural evolution of cementitious materials during hydration process and to analyse modifications due to drying effect. Two durability parameters are studied: water content and porosity. An original way for the investigation is to use Magnetic Resonance Imaging MRI. First, we present a bibliographic synthesis for cementitious materials and for MRI applied on porous media to analyse proton density linked to water content and relaxation NMR which gives information of pore size distribution. Then, results obtained with relaxation and MRI, are compared and identified with common destructive methods commonly used in civilengineering. Finally we analyze two important phenomena on cementitious materials: hydration process and hydration coupled to dryingMARNE-LA-VALLEE-ENPC-BIBL. (774682303) / SudocSudocFranceF

In vivo mapping of tumor oxygen consumption using (19)F MRI relaxometry

Recently, we have developed a new electron paramagnetic resonance (EPR) protocol in order to estimate tissue oxygen consumption in vivo. Because it is crucial to probe the heterogeneity of response in tumors, the aim of this study was to apply our protocol, together with (19)F MRI relaxometry, to the mapping of the oxygen consumption in tumors. The protocol includes the continuous measurement of tumor pO(2) during the following respiratory challenge: (i) basal values during air breathing; (ii) increasing pO(2) values during carbogen breathing until saturation of tissue with oxygen; (iii) switching back to air breathing. We have demonstrated previously using EPR oximetry that the kinetics of return to the basal value after oxygen saturation are mainly governed by tissue oxygen consumption. This challenge was applied in hyperthyroid mice (generated by chronic treatment with L-thyroxine) and control mice, as hyperthyroidism is known to dramatically affect the oxygen consumption rate of tumor cells. Our recently developed snapshot inversion recovery MRI fluorocarbon oximetry technique allowed the pO(2) return kinetics to be measured with a high temporal resolution. The kinetic constants (i.e. oxygen consumption rates) were higher for tumors from hyperthyroid mice than from control mice, data that are consistent with our previous EPR study. The corresponding histograms of the (19)F MRI data showed that the kinetic constants displayed a shift to the right for the hyperthyroid group, indicating a higher oxygen consumption in these tumors. The color maps showed a large heterogeneity in terms of oxygen consumption rate within a tumor. In conclusion, (19)F MRI relaxometry allows the noninvasive mapping of the oxygen consumption in tumors. The ability to assess the heterogeneity of tumor response is critical in order to identify potential tumor regions that might be resistant to treatment and therefore produce a poor response to therapy. Copyright © 2010 John Wiley & Sons, Ltd

Comparison between NMR non destructive method and common invasive methods used for concrete structuration evolution

A better understanding of the cement hydration evolution and of the development of cementitious materials microstructure at early age is very important for improving concrete durability. The microstructure, which depends on various factors (water-cement ratio, curing conditions ), is characterized by water content and pore-size distribution. The originality of this study is to compare relaxation and MRI along with common destructive methods (capacitive method, mass loss by heating or freeze drying ) to characterize cement porosity and free water content. With this approach, common techniques are used to identify phenomena observed by NMR and also provide validation of NMR as a tool to investigate cement hydration. The NMR technique is unique and allows to follow a same sample through time at a very early age and in a non-destructive way. Results obtained by these different techniques show a good correlation. Furthermore, this novel approach shows that NMR gives complementary information, and thus provides a complete study of cement hydration

Drying effect on cement paste porosity at early age observed by NMR methods

International audienceNuclear Magnetic Resonance (NMR) methods (imaging and relaxation time) allow to study the water content and the pore size distribution in cementitious materials. Hydration of cement pastes with two water to cement ratios W/C (W/C=0.4 and W/C=0.45) has been studied under two conditions (with drying or without drying) at early age. The objectives of this study were, firstly (i) to determine the water content and the drying mechanisms with Magnetic Resonance Imaging (MRI) and to validate these results with oven-drying methods and secondly (ii) to analyse the cement paste porosity modifications due to drying exposure with distribution of T1 relaxation times, which are compared to by Mercury Intrusion Porosimetry and N2 gas adsorption measurements. The results of this study highlight the pertinence of NMR and associated methods to understand mechanisms of hydration of cementitious materials and especially the influence of drying on hydration process and on microstructure of the materials

A groupwise registration and tractography framework for cardiac myofiber architecture description by diffusion MRI: An application to the ventricular junctions.

International audienceBackground: Knowledge of the normal myocardial–myocyte orientation could theoretically allow the definition of relevant quantitative biomarkers in clinical routine to diagnose heart pathologies. A whole heart diffusion tensor template representative of the global myofiber organization over species is therefore crucial for comparisons across populations. In this study, we developed a groupwise registration and tractography framework to resolve the global myofiber arrangement of large mammalian sheep hearts. To demonstrate the potential application of the proposed method, a novel description of sub-regions in the intraventricular septum is presented.Methods: Three explanted sheep (ovine) hearts (size ~12×8×6 cm3, heart weight ~ 150 g) were perfused with contrast agent and fixative and imaged in a 9.4T magnet. A group-wise registration of high-resolution anatomical and diffusion-weighted images were performed to generate anatomical and diffusion tensor templates. Diffusion tensor metrics (eigenvalues, eigenvectors, fractional anisotropy …) were computed to provide a quantitative and spatially-resolved analysis of cardiac microstructure. Then tractography was performed using deterministic and probabilistic algorithms and used for different purposes: i) Visualization of myofiber architecture, ii) Segmentation of sub-area depicting the same fiber organization, iii) Seeding and Tract Editing. Finally, dissection was performed to confirm the existence of macroscopic structures identified in the diffusion tensor template.Results: The template creation takes advantage of high-resolution anatomical and diffusion-weighted images obtained at an isotropic resolution of 150 μm and 600 μm respectively, covering ventricles and atria and providing information on the normal myocardial architecture. The diffusion metric distributions from the template were found close to the one of the individual samples validating the registration procedure. Small new sub-regions exhibiting spatially sharp variations in fiber orientation close to the junctions of the septum and ventricles were identified. Each substructure was defined and represented using streamlines. The existence of a fiber-bundles in the posterior junction was validated by anatomical dissection. A complex structural organization of the anterior junction in comparison to the posterior junction was evidenced by the high-resolution acquisition.Conclusions: A new framework combining cardiac template generation and tractography was applied on the whole sheep heart. The framework can be used for anatomical investigation, characterization of microstructure and visualization of myofiber orientation across samples. Finally, a novel description of the ventricular junction in large mammalian sheep hearts was proposed

Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19F MRI

PURPOSE: Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and may be a poorly appreciated therapeutic problem as it can be associated with resistance to radiation therapy, impaired delivery of chemotherapeutic agents, or metastasis development. The objective of the present study was to use MR 19F relaxometry maps to analyze the spontaneous fluctuations of partial pressure of oxygen (pO2) over time in experimental tumors. METHODS: The pO2 maps were generated after direct intratumoral administration of a fluorine compound (hexafluorobenzene) whose relaxation rate (1/T1) is proportional to the % O2. The authors used a SNAP inversion-recovery sequence at 4.7 T to acquire parametric images of the T1 relaxation time with a high spatial and temporal resolution. Homemade routines were developed to perform regions of interest analysis, as well as pixel by pixel analysis of pO2 over time. RESULTS: The authors were able to quantify and probe the heterogeneity of spontaneous fluctuations in tumor pO2: (i) Spontaneous fluctuations in pO2 occurred regardless of the basal oxygenation state (i.e., both in oxygenated and in hypoxic regions) and (ii) spontaneous fluctuations occurred at a rate of 1 cycle/12-47 min. For validation, the analysis was performed in dead mice for which acute changes did not occur. The authors thereby demonstrated that 19F MRI technique is sensitive to acute change in pO2 in tumors. CONCLUSIONS: This is the first approach that allows quantitative minimally invasive measurement of the spontaneous fluctuations of tumor oxygenation using a look-locker approach (e.g., SNAP IR). This approach could be an important tool to characterize the phenomenon of tumor acute hypoxia, to understand its physiopathology, and to improve therapies

A groupwise registration and tractography framework for cardiac myofiber architecture description by diffusion MRI: an application to the ventricular junctions

Abstract Background Knowledge of the normal myocardial–myocyte orientation could theoretically allow the definition of relevant quantitative biomarkers in clinical routine to diagnose heart pathologies. A whole heart diffusion tensor template representative of the global myofiber organization over species is therefore crucial for comparisons across populations. In this study, we developed a groupwise registration and tractography framework to resolve the global myofiber arrangement of large mammalian sheep hearts. To demonstrate the potential application of the proposed method, a novel description of sub-regions in the intraventricular septum is presented. Methods Three explanted sheep (ovine) hearts (size ~12×8×6 cm3, heart weight ~ 150 g) were perfused with contrast agent and fixative and imaged in a 9.4T magnet. A group-wise registration of high-resolution anatomical and diffusion-weighted images were performed to generate anatomical and diffusion tensor templates. Diffusion tensor metrics (eigenvalues, eigenvectors, fractional anisotropy …) were computed to provide a quantitative and spatially-resolved analysis of cardiac microstructure. Then tractography was performed using deterministic and probabilistic algorithms and used for different purposes: i) Visualization of myofiber architecture, ii) Segmentation of sub-area depicting the same fiber organization, iii) Seeding and Tract Editing. Finally, dissection was performed to confirm the existence of macroscopic structures identified in the diffusion tensor template. Results The template creation takes advantage of high-resolution anatomical and diffusion-weighted images obtained at an isotropic resolution of 150 μm and 600 μm respectively, covering ventricles and atria and providing information on the normal myocardial architecture. The diffusion metric distributions from the template were found close to the one of the individual samples validating the registration procedure. Small new sub-regions exhibiting spatially sharp variations in fiber orientation close to the junctions of the septum and ventricles were identified. Each substructure was defined and represented using streamlines. The existence of a fiber-bundles in the posterior junction was validated by anatomical dissection. A complex structural organization of the anterior junction in comparison to the posterior junction was evidenced by the high-resolution acquisition. Conclusions A new framework combining cardiac template generation and tractography was applied on the whole sheep heart. The framework can be used for anatomical investigation, characterization of microstructure and visualization of myofiber orientation across samples. Finally, a novel description of the ventricular junction in large mammalian sheep hearts was proposed