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L'obésité (Ob) est un facteur de risque majeur pour l'arthrose (OA). L'angiogenèse de l'os sous-chondral est impliquée dans la pathophysiologie de l'OA et peut réagir différemment aux facteurs de promotion de l'OA. L’objectif était de discriminer le rôle respectif de la charge liée au surpoids et des troubles métaboliques sur la dégradation articulaire et l'angiogenèse, dans un modèle de souris arthrosique. Des souris C57BL/6j ont subi une déstabilisation chirurgicale du ménisque médiale pour induire l'OA. Des souris OA-Mince ont ensuite été soumises à une hypergravité pour imiter les effets du surpoids. Les autres souris ont été conservées à 1g. Des souris OA-mince et des souris OA-Ob ont été traitées avec un anti-VEGF. Après la perfusion de baryum, le genou droit a été imagé et la microstructure osseuse, la moelle osseuse et les réseaux vasculaires sous-chondraux ont été quantifiés. L'histologie quantitative de l'os sous-chondral a été effectué. La dégradation du cartilage articulaire était similaire entre les groupes OA. L'hypergravité n'a pas aggravé l'amincissement du cartilage induit par l’OA mais a empêché l'épaississement lié à l'OA de la plaque osseuse sous-chondrale. Les souris OA-Ob avaient un volume osseux trabéculaire épiphysaire inférieur à celui des souris Mince-OA. L’OA a induit une angiogenèse à travers la plaque sous-chondrale dans les groupes OA-Mince 1g et 2g. En revanche, la densité vasculaire de la Mo était plus faible chez les OA-Ob que chez OA-Mince. L'obésité et le 2g ont eu des effets opposés sur la taille des vaisseaux. Le bevacizumab a empêché l'angiogenèse induite par l'OA dans le groupe OA-Mince mais n'a eu aucun effet dans le groupe Ob. / Obesity is a major risk factor for osteoarthritis (OA). Subchondral bone angiogenesis is involved in OA pathophysiology and may respond differently to OA promoting factors. Aim was to discriminate the respective role of overweight-related-load and of metabolic disorders due to fat accumulation, in joint degradation and angiogenesis, in a mouse model of surgically Induced knee osteoarthritis. C57BL/6j male mice underwent surgical medial meniscus destabilization (MMD) to induce OA and Lean mice were sham operated (Sham-lean). At 2 Mo, gps were fed with high fat diet to induce insulino-resistance and obesity (Ob). OA-Lean mice were then submitted to 2g hypergravity in a centrifuge to mimic the effects of overweight. OA-lean mice and OA-Ob mice were treated with an anti-VEGF. After barium infusion, the right knee was imaged by high-resolution and bone microstructure, bone marrow (bm) and subchrondral vascular networks were quantified. After MMA embedding, OARSI scoring and subchondral bone quantitative histology were then carried out at the medial tibia plateau.Articular cartilage degradation was similar between the OA groups.

<p>Many implanted devices fail due to the formation of an avascular capsule. Fat is known to promote healing and vascularization. It is possible that isolating and attaching ASCs (adipose stem cells) to an implanted device improves the healing in the adjacent tissue. </p><p> Various attachment methods were studied, and the fibronectin treatment was found comparable to or better than other treatments. Next, bare and ASC coated polyurethane were implanted into rats. The fibrous capsule surrounding the bare polyurethane was thicker and contained more collagen at 8 weeks. Additionally, the microvessel density in the tissue surrounding the ASC coated polyurethane was significantly higher at 4 and 8 weeks. Quantification of glucose sensor response following ASC attachment for 1 week found no measurable significant differences in function.</p><p> The bioluminescence technique, which quantifies the tissue glucose concentration around the implant at the moment of freezing, was used to determine if ASC attachment to biomaterials impacts the tissue glucose concentration profile. ASC attachment to polyurethane and to glucose sensors did not significantly change the glucose profiles in the tissue. However, a quantifiable glucose concentration profile was observed around all glucose sensors.</p><p> The final experiments were performed to identify a possible mechanism that adipose tissue uses to alter the foreign body response. In vitro experiments showed that VEGF (VEGF-A specifically) secretion following ASC attachment to polyurethane was 10-20 times higher than with fibroblast attachment after three days and 40-70 times higher after six days. This high secretion of VEGF would likely have in vivo physiological affects on microvasculature.</p><p> In conclusion, the attachment of ASCs to polyurethane reduced the thickness and collagen content of the fibrous capsule surrounding ASC coated implants and increased the microvessel density in adjacent tissue. In addition, ASC attachment did not enhance glucose sensor function, nor did it decrease the glucose concentration in the adjacent tissue. Finally, ASCs were found to secrete high amounts of pro-vascular cytokines, which likely plays a key role in the observed improvement of the foreign body response.</p> / Dissertation

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19398号 / 医博第4049号 / 新制||医||1012(附属図書館) / 32423 / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 妻木 範行, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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In human pregnancy, the feto-placental vessels are crucial for efficient materno-fetal transfer; hence they play a pivotal role in the pathogenesis of fetal growth restriction (FGR). We, as well as other research groups, have observed abnormalities in the FGR feto-placental vasculature, which, though inconclusive, were suggestive of a state of panhypovascularity. The goal of the work presented in this thesis was to investigate this. We hypothesised that the placenta may be panhypovascular in FGR due to failed angiogenesis; and enhancing angiogenesis in the placenta may improve fetal growth. Custom-designed techniques including advanced imaging, computer-aided analyses and tube-forming experiments were employed to compare feto-placental vessels and endothelial cells in placentas from normal and FGR-complicated pregnancies while aiming to answer two main research questions: (i) is the FGR placenta panhypovascular? (ii) can angiogenesis be induced or enhanced to improve placental vascularity?Findings include: (i) shorter arterial [p = 0.03 and 0.009 when data adjusted for placental surface area (PA) and weight (PW) respectively] and longer venous path [p = 0.05 and 0.03, adjusted for PA and PW respectively] in FGR placentas though no difference in the total number of arterial or venous branches, diameter, and tortuosity of the vessels compared to normal; (ii) altered angiogenic behaviour/response of FGR placental endothelial cells following in vitro pharmacological manipulation of WNT signalling; (iii) human placental endothelial cells are capable of regaining their angiogenic potential following withdrawal of WNT inhibition. These findings discount the hypothesis of panhypovascularity in FGR placentas, but identify additional, previously unreported, feto-placental vascular abnormalities associated with FGR. Also, the findings provide evidence that impairment of WNT signalling may play a role in defective angiogenesis and consequent dysvascularity in the FGR placenta. The evidence suggests the WNT pathway should be explored as a potential new target for therapeutic interventions to correct placental dysvascularity in FGR.

Diabetes Mellitus is a group of complex and heterogeneous metabolic disorders characterized by hyperglycemia. Even though the condition has been extensively studied, its causes and complex pathologies are still not fully understood. The occurring damage to the pancreatic islets is strikingly heterogeneous. In type 1 diabetes, the insulin producing beta cells are all destroyed within some islets, and similarly in type 2 diabetes, some islets may be severely affected by amyloid. At the same time other islets, in the near vicinity of the ones that are affected by disease, may appear fully normal in both diseases. Little is known about this heterogeneity in susceptibility to disease between pancreatic islets. This thesis examines the physiological and pathophysiological characteristics of islet subpopulations. Two subpopulations of islets were studied; one constituting highly vascularized islets with superior beta cell functionality, and one of low-oxygenated islets with low metabolic activity. The highly functional islets were found to be more susceptible to cellular stress both in vitro and in vivo, and developed more islet amyloid when metabolically challenged. Highly functional islets preferentially had a direct venous drainage, facilitating the distribution of islet hormones to the peripheral tissues. Further, these islets had an increased capacity for insulin secretion at low glucose levels, a response that was observed abolished in patients with recent onset type 1 diabetes.  The second investigated islet subpopulation, low-oxygenated islets, was found to be an over time stable subpopulation of islets with low vascular density and beta cell proliferation. In summary, two subpopulations of islets can be identified in the pancreas based on dissimilarities in vascular support and blood flow. These subpopulations appear to have different physiological functions of importance for the maintenance of glucose homeostasis. However, they also seem to differ in vulnerability, and a preferential death of the highly functional islets may accelerate the progression of both type 1 and type 2 diabetes.

Background: The relevance of drusen-like deposits (DLD) in patients with systemic lupus erythematosus (SLE) is to a large extent uncertain. Their genesis is proposed to be correlated to immune-complex and complement depositions in the framework of SLE. The intention of this study was to determine potential morphological differences in the choroid and retina as well as potential microvascular changes comparing two cohorts of SLE patients divergent in the presence or absence of DLD using multimodal imaging. Methods: Both eyes of 16 SLE patients with DLD were compared to an age- and sex-matched control-group consisting of 16 SLE patients without detectable DLD. Both cohorts were treated with hydroxychloroquine (HCQ) and did not differ in the treatment duration or dosage. Using spectral-domain optical coherence tomography (SD-OCT) choroidal volume measures, choroidal vascularity indices (CVI) and retinal layer segmentation was performed and compared. In addition, by the exploitation of optical coherence tomography angiography vascular density, perfusion density of superficial and deep retinal capillary plexuses and the choriocapillaris were analyzed. For the choroidal OCT-scans, a subset of 51 healthy individuals served as a reference-group. Results: CVI measures revealed a significant reduction in eyes with DLD compared to healthy controls (0.56 (0.54−0.59) versus 0.58 (0.57−0.59) (p = 0.018) and 0.56 (0.54−0.58) versus 0.58 (0.57−0.60) (p < 0.001)). The photoreceptor cell layer presented significant thinning in both eyes of subjects with DLD compared to control subjects without DLD (68.8 ± 7.7 µm vs. 77.1 ± 7.3 µm for right eyes, p = 0.008, and 66.5 ± 10.5 µm vs. 76.1 ± 6.3 µm for left eyes, p = 0.011). OCTA scans revealed no significant changes, yet there could be observed numerically lower values in the capillary plexuses of the retina in eyes with DLD than in eyes without DLD. Conclusions: Our results illustrated significant alterations in the choroidal and retinal analyzes, suggesting a correlation between DLD and the progression of inflammatory processes in the course of SLE leading to retinal degeneration. For this reason, DLD could serve as a biomarker for a more active state of disease.

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