Microvascular permeability is a pharmacologic indicator of tumor response to therapy, and it is expected that this biomarker will evolve into a clinical surrogate endpoint and be integrated into protocols for determining patient response to antiangiogenic or antivascular therapies. The goal of this research is to develop a method by which microvascular permeability (Ktrans) and vascular volume (vp) as measured by DCE-MRI were directly compared to the same parameters measured by intravital fluorescence microscopy in an MRI-compatible window chamber model. Dynamic contrast enhanced-MRI (DCE-MRI) is a non-invasive, clinically useful imaging approach that has been used extensively to measure active changes in tumor microvascular hemodynamics. However, uncertainties exist in DCE-MRI as it does not interrogate the contrast reagent (CR) itself, but the effect of the CR on tissue water relaxivity. Thus, direct comparison of DCE-MRI with a more quantitative measure would help better define the derived parameters. The combined imaging system was able to obtain both dynamic contrast-enhanced MRI data high spatio-termporal resolution fluorescence data following injection of fluorescent and gadolinium co-labeled albumin. This approach allowed for the cross-validation of vascular permeability data, in relation tumor growth, angiogenesis and response to therapy in both imaging systems.

A la suite d'une lésion nerveuse périphérique, de multiples altérations cellulaires et moléculaires participent à la régénération physiologique du nerf, mais induisent dans certains cas le développement d'une cicatrisation dysfonctionnelle et l'apparition d'une douleur neuropathique chronique. La régulation de la perméabilité vasculaire endoneurale du nerf lésé joue un rôle essentiel dans ces phénomènes de cicatrisation nerveuse, via notamment l'infiltration locale d'immunocytes. L'objectif de ce travail était d'étudier le rôle spécifique de l'altération de la barrière hémato-nerveuse (BHN) au niveau du site lésé dans le développement des douleurs neuropathiques périphériques post-traumatiques. Nous avons montré à l'aide de modèles de constriction chronique du nerf sciatique et/ou infra-orbitaire que la disruption précoce de la BHN est un évènement clé de la neuropathie, favorisant l'infiltration locale de substances algogènes et d'immunocytes induisant une neuroinflammation, une sensibilisation périphérique et la neuropathie. L'altération des voies de signalisation Sonic Hedgehog, Wnt/?-caténine et TLR4 au niveau des cellules endothéliales endoneurales, favorise cette disruption en diminuant la synthèse des protéines de jonctions serrées, molécules clés de l'intégrité de la BHN. De plus, l'implication différentielle de ces voies dans des modèles de neurite et de neuropathie apporte un éclairage nouveau à la transition phénotypique entre neurite et neuropathie : alors que la neurite s'accompagne d'une perméabilité vasculaire endoneurale réversible, la neuropathie pourrait être considérée comme une pathologie de la perméabilité vasculaire chronique irréversible. / Following peripheral nerve injury, multiple cellular and molecular alterations occur within the nerve’s parenchyma, participating in physiological healing of the nerve, but can also lead to the development of dysfunctional nerve healing, translating as chronic neuropathic pain. The regulation of endoneurial microvascular permeability within the injured nerve plays a pivotal rôle in physiological and pathological nerve healing, notably via the local infiltration of pro-regenerative immunocytes. The main goal of this work was to study the specific role of local blood-nerve barrier disruption in the development of painful post-traumatic peripheral neuropathy. In sciatic nerve and/or infra-orbital nerve chronic constriction injury models, we showed that early disruption of the blood-nerve barrier is a key event in the development of neuropathy, allowing local infiltration of algogenic substances and immunocytes within the nerve’s parenchyma, responsible for local neuroinflammation, peripheral sensitization and peripheral neuropathic pain development. Among the homeostatic regulatory mecanisms of this barrier, the alteration of Sonic Hedgehog, Wnt/β-catenin and TLR4 signaling pathways in endoneurial endothelial cells, mediates the disruption of the blood-nerve barrier by downregulating key tight-junction proteins. Furthermore, the differential implication of these signaling pathways in models of neuritis and neuropathy shed light on the phenotypical transition between neuritis and neuropathy : As neuritis is associated with reversible endoneurial vascular permeability, neuropathy could be considered a disease of irreversible chronic vascular permeability.