ED Sciences de la Vie et de la Santé
Role of microvascular disease in the pathophysiology of peripheral artery disease
by Ninon FOUSSARD (Biologie des maladies cardiovasculaires)
The defense will take place at 14h00 - Salle de séminaire de l'INSERM U1034 INSERM U1034 1 Avenue Magellan 33600 Pessac
in front of the jury composed of
- Marie-Ange RENAULT - Chargée de recherche - Université de Bordeaux - Directeur de these
- Dominique SIGAUDO-ROUSSEL - Directrice de recherche - Université Claude Bernard Lyon 1 - Rapporteur
- Benoît HO-TIN-NOE - Directeur de recherche - Université Paris cité - Rapporteur
- Jean-François GAUTIER - Professeur des universités - praticien hospitalier - Université Paris cité - Examinateur
Chronic limb-threatening ischemia (CLTI), a macrovascular disease, is the final stage of lower-limb extremity arterial disease (LEAD). This stage is at risk of amputation. This risk is notably due to a lack of understanding of its pathophysiology and, consequently, to the absence of effective therapies. Diabetes is a risk factor in the progression from LEAD to CLTI, but also in microvascular disease. We hypothesize that studying the mechanisms by which diabetes aggravates LEAD could provide a better understanding of the pathophysiology of CLTI. We assume that impaired perfusion at the microvascular level following capillary endothelial dysfunction could contribute to the worsening of LEAD towards CLTI. The aim is to identify new mechanisms responsible for the aggravation of LEAD by comparing the recovery of hindlimb ischemia in diabetic versus non-diabetic mice, and to explore the potential contribution of microvascular damage to CLTI in a diabetic context. CLTI was induced by double ligation and excision of the left posterior femoral artery in 2 mouse models representing type 2 diabetes, compared with their non-diabetic controls: 1) Leprdb/db mice and 2) C57BL6/J with a high-fat diet and low-dose streptozotocin injections. Under CLTI conditions, i.e. at postoperative Day 28, diabetic versus non-diabetic mice showed impaired perfusion of the whole ischemic limb without impaired angiogenesis, demonstrating that impaired reperfusion is not associated with a defect in angiogenesis. These capillaries, which are present, are nevertheless dysfunctional in the diabetic context, presenting a decrease in the velocity of circulating leukocytes, and their perfusion by lectin-BS1-FITC. This alteration was associated with significant capillary endothelial dysfunction, with increased expression of circulating leukocyte adhesion molecules, notably ICAM1. Furthermore, increased ICAM1 was also found in muscles from CLTI patients, compared with healthy muscles. To assess the impact of endothelial dysfunction in CLTI of diabetic mice, we first targeted it with praliciguat, a soluble Guanylate Cyclase stimulator. Treatment with praliciguat versus placebo in ischemic diabetic mice improved microvascular perfusion (leukocyte velocity in capillaries, number of capillaries perfused) at D28, by improving arteriolar vasodilation but also by indirectly decreasing ICAM1 via myocytes. As expected, angiogenesis was unaffected. To target more specifically the effect of ICAM1 on microvascular perfusion, we then used a monoclonal antibody blocking versus its isotype. Injections were performed from D14 to D28, to avoid affecting the early recruitment of inflammatory cells required for angiogenesis and myogenesis. The anti-ICAM1 antibody also improved microvascular perfusion parameters without affecting angiogenesis. Thus, this study suggests that in the chronic stage of ischemia, it is probable that the blood flow recovery is due to maturation and improved functionality of the new vasculature formed by angiogenesis, and that this maturation stage is deficient in diabetic mice. Overexpression of ICAM1 appears to compromise recovery from CLTI by impairing microvessel perfusion and seems to be a potential therapeutic target for CLTI.
ED Sciences Physiques et de l'Ingénieur
Higgs mode in superconducting heterojunctions
by Pierre VALLET (Laboratoire Ondes et Matière d'Aquitaine)
The defense will take place at 14h00 - Bât A29 Amphi A 351 cours de la Libération 33405 TALENCE
in front of the jury composed of
- Jérôme CAYSSOL - Professeur - Université de Bordeaux - Directeur de these
- Marco APRILI - Directeur de recherche - LPS Orsay - Rapporteur
- Manuel HOUZET - Directeur de recherche - CEA Grenoble - Rapporteur
- Hélène BOUCHIAT - Directrice de recherche - LPS Orsay - Examinateur
- Luka TRIFUNOVIC - Chargé de recherche - Laboratoire de Physique Théorique Toulouse - Examinateur
- Philippe TAMARAT - Professeur - LP2N Bordeaux - Examinateur
The development of THz technologies over the last ten years has enabled the direct detection of the Higgs mode in superconductors. In this thesis, we propose to study theoretically the transport of three superconducting heterojunction systems exhibiting Higgs mode signatures. We first investigated the possibility of exciting the Higgs mode in a clean superconductor (in the absence of impurities) using THz irradiation. This problem is still being debated today, with several contradictory results predicting the possibility and impossibility of exciting the mode. In this thesis, we have demonstrated that such excitation is possible in the presence of a Cooper pair depairing mechanism. In the absence of such a mechanism, the Higgs mode is identically zero in a clean system. Next, we showed in a quasi-classical approach that there is a resonant signature of the Higgs mode in the ac current of a NIS clean tunnel junction, the Higgs mode itself being resonant at the frequency equal to the superconducting gap. To continue our study of clean system, we turned our attention to an NSN ballistic junction in the Floquet formalism. At NS interfaces, it is known that an electron can be reflected into a hole by the Andreev reflection mechanism. The interaction of this effect with the presence of the Higgs mode produces a Higgs signature in the differential conductance of the junction in the form of a plateau. The last system we studied was a Josephson junction. The interaction between the Higgs mode and the Josephson effect produces a number of detectable effects due to the Higgs mode: a dc current peak, an ac current in the absence of a voltage difference in the junction, or the presence of peaks in the ac current, a product of the interaction between the Higgs mode and photon-assisted transport.