{"id":{"repo_id":"sherbrooke","oai_identifier":"oai:usherbrooke.scholaris.ca:11143/20439"},"canonical_url":"https://search.dev.ndltd.org/etd/sherbrooke/oai:usherbrooke.scholaris.ca:11143/20439","repository":{"repo_id":"sherbrooke","name":"Université de Sherbrooke","base_url":"https://usherbrooke.scholaris.ca/server/oai/request"},"display":{"title":"Délétion endothéliale de SHP-1 prévient la sénescence et rétablit l’angiogenèse des cellules endothéliales vasculaires en condition de diabète","abstract":"Diabetes causes a dysregulation of angiogenesis, an essential process for the formation of new blood vessels following ischemia, and enhances vascular ageing (senescence), increasing the risk of amputation for patients with diabetes. Our laboratory has shown that the increased expression of protein tyrosine phosphatase SHP-1 in the ischemic muscle of diabetic mice was associated with higher phosphatase activity in the endothelial cells (EC) exposed to high concentrations of glucose. Our objective was to evaluate the role of SHP-1 in the regulation of the angiogenic process and senescence in the EC and ischemic muscle of diabetic mice. Diabetic (DM) and non-diabetic (NDM) mice with or without EC-specific deletion of SHP-1 underwent femoral artery ligation. Blood reperfusion was measured over a 4-week period using Doppler laser imaging and muscles were harvested for protein analysis. Histological staining was also performed in the ischemic muscle of all groups of mice. In vitro, EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations and placed under a hypoxic environment (1% O2) in the presence or absence of the angiogenic factor VEGF (10 ng/mL) with or without overexpression of dominant negative of SHP-1. Four weeks after surgery, blood reperfusion, limb function (distance traveled in a running wheel) and formation of new collateral vessels in ischemic muscle were significantly reduced in DM mice compared to NDM mice. These effects of diabetes were prevented by the EC-specific deletion of SHP-1. In vitro, the use of a dominant negative SHP-1 reversed HG-induced inhibition of VEGF actions in EC by restoring phosphorylation of VEGFR-2 and Akt. Meanwhile, inhibition of SHP-1 prevented the increased expression of p21 and β-galactosidase as well as the reduction of Nrf2, three senescence markers, caused by HG exposure. In conclusion, EC-specific deletion of SHP-1 prevented the effects of diabetes on senescence and angiogenesis leading to improved blood reperfusion and limb function in diabetic mice.","abstract_html":"Diabetes causes a dysregulation of angiogenesis, an essential process for the formation of new blood vessels following ischemia, and enhances vascular ageing (senescence), increasing the risk of amputation for patients with diabetes. Our laboratory has shown that the increased expression of protein tyrosine phosphatase SHP-1 in the ischemic muscle of diabetic mice was associated with higher phosphatase activity in the endothelial cells (EC) exposed to high concentrations of glucose. Our objective was to evaluate the role of SHP-1 in the regulation of the angiogenic process and senescence in the EC and ischemic muscle of diabetic mice. Diabetic (DM) and non-diabetic (NDM) mice with or without EC-specific deletion of SHP-1 underwent femoral artery ligation. Blood reperfusion was measured over a 4-week period using Doppler laser imaging and muscles were harvested for protein analysis. Histological staining was also performed in the ischemic muscle of all groups of mice. In vitro, EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations and placed under a hypoxic environment (1% O2) in the presence or absence of the angiogenic factor VEGF (10 ng/mL) with or without overexpression of dominant negative of SHP-1. Four weeks after surgery, blood reperfusion, limb function (distance traveled in a running wheel) and formation of new collateral vessels in ischemic muscle were significantly reduced in DM mice compared to NDM mice. These effects of diabetes were prevented by the EC-specific deletion of SHP-1. In vitro, the use of a dominant negative SHP-1 reversed HG-induced inhibition of VEGF actions in EC by restoring phosphorylation of VEGFR-2 and Akt. Meanwhile, inhibition of SHP-1 prevented the increased expression of p21 and β-galactosidase as well as the reduction of Nrf2, three senescence markers, caused by HG exposure. In conclusion, EC-specific deletion of SHP-1 prevented the effects of diabetes on senescence and angiogenesis leading to improved blood reperfusion and limb function in diabetic mice.","abstract_has_math":false,"creators":["Nadeau, Alexandre"],"institution":"Université de Sherbrooke","degree_name":"M. Sc.","degree_level":"Maîtrise","degree_discipline":"Physiologie","degree_department":null,"school":null,"contributors":[],"advisors":["Geraldes, Pedro Miguel"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023","date_published":"2023","updated_at":"2026-07-27T21:07:32Z","subjects":["Maladie des artères périphériques","Diabète","Sénescence","Angiogenèse","SHP-1","VEGF","p21","Peripheral arterial disease","Diabetes","Senescence","Angiogenesis"],"languages":["fr"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/11143/20439","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Geraldes, Pedro Miguel"]},{"key":"dc:creator","label":"Author","values":["Nadeau, Alexandre"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-07-06T13:39:17Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-07-06T13:39:17Z"]},{"key":"dc:date.issued","label":"Date","values":["2023"]},{"key":"dc:publisher","label":"Institution","values":["Université de Sherbrooke"]},{"key":"dc:type","label":"Dc Type","values":["Mémoire de maîtrise"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Physiologie"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Maîtrise"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M. 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Our laboratory has shown that the increased expression of protein tyrosine phosphatase SHP-1 in the ischemic muscle of diabetic mice was associated with higher phosphatase activity in the endothelial cells (EC) exposed to high concentrations of glucose. Our objective was to evaluate the role of SHP-1 in the regulation of the angiogenic process and senescence in the EC and ischemic muscle of diabetic mice. Diabetic (DM) and non-diabetic (NDM) mice with or without EC-specific deletion of SHP-1 underwent femoral artery ligation. Blood reperfusion was measured over a 4-week period using Doppler laser imaging and muscles were harvested for protein analysis. Histological staining was also performed in the ischemic muscle of all groups of mice. In vitro, EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations and placed under a hypoxic environment (1% O2) in the presence or absence of the angiogenic factor VEGF (10 ng/mL) with or without overexpression of dominant negative of SHP-1. Four weeks after surgery, blood reperfusion, limb function (distance traveled in a running wheel) and formation of new collateral vessels in ischemic muscle were significantly reduced in DM mice compared to NDM mice. These effects of diabetes were prevented by the EC-specific deletion of SHP-1. In vitro, the use of a dominant negative SHP-1 reversed HG-induced inhibition of VEGF actions in EC by restoring phosphorylation of VEGFR-2 and Akt. Meanwhile, inhibition of SHP-1 prevented the increased expression of p21 and β-galactosidase as well as the reduction of Nrf2, three senescence markers, caused by HG exposure. In conclusion, EC-specific deletion of SHP-1 prevented the effects of diabetes on senescence and angiogenesis leading to improved blood reperfusion and limb function in diabetic mice.","Le diabète cause une dérégulation de l’angiogenèse, un processus essentiel à la formation de nouveaux vaisseaux suite une ischémie et augmente le vieillissement vasculaire (sénescence) contribuant à un risque élevé d’amputation. Notre laboratoire a montré une augmentation de l’expression de la protéine tyrosine phosphatase SHP-1 dans le muscle ischémique de souris diabétiques, qui se traduit par une augmentation de son activité phosphatase dans les cellules endothéliales (CE) exposées à une concentration élevée de glucose. Notre objectif était d’évaluer le rôle de SHP-1 dans la régulation du processus angiogénique et de la sénescence dans les CE et du muscle ischémique diabétique. Des souris diabétiques (DM) et non-diabétiques (NDM) avec ou sans délétion de SHP-1 spécifique aux CEs ont subi une ligature de l’artère fémorale. La reperfusion sanguine a été mesurée sur une période de 4 semaines à l’aide d’un laser Doppler et les muscles ont été récoltés pour analyses protéiques. Des marquages histologiques ont également été effectués dans les muscles ischémiques. In vitro, des CE ont été exposées à des concentrations normales (5.6 mM; NG) ou élevées (25 mM; HG) de glucose et mises en condition d’hypoxie (1% d’O2) en présence ou non du facteur angiogénique VEGF (10 ng/mL) avec ou sans surexpression d’un adénovirus dominant négatif de SHP-1. Quatre semaines suivant la chirurgie, la reperfusion sanguine, la fonction motrice (distance parcourue en cage à roue) et la formation de nouveaux vaisseaux collatéraux dans le muscle ischémique étaient réduites significativement chez les souris DM comparées aux souris NDM, des effets rétablis par la délétion spécifique dans les CE de SHP-1. In vitro, l’utilisation d’un dominant négatif de SHP-1 a renversé les effets néfastes du HG sur l’angiogenèse des CE induits par le VEGF en rétablissant la phosphorylation du récepteur VEGFR-2 ainsi que Akt. En parallèle, l’inhibition de SHP-1 a empêché l’augmentation de l’expression de p21 et de la bêta-galactosidase ainsi que la réduction de Nrf2, tous des marqueurs de sénescence, causées par l’exposition au HG. En conclusion, la délétion spécifique aux cellules endothéliales de SHP-1 a permis de renverser les effets du diabète sur la sénescence et l’angiogenèse permettant d’améliorer la reperfusion sanguine et la fonction motrice chez les souris diabétiques."]},{"key":"dc:title","label":"Title","values":["Délétion endothéliale de SHP-1 prévient la sénescence et rétablit l’angiogenèse des cellules endothéliales vasculaires en condition de diabète"]}]}],"canonical_facts":{"dc:contributor.advisor":["Geraldes, Pedro Miguel"],"dc:creator":["Nadeau, Alexandre"],"dc:date.accessioned":["2023-07-06T13:39:17Z"],"dc:date.available":["2023-07-06T13:39:17Z"],"dc:date.issued":["2023"],"dc:description.abstract":["Diabetes causes a dysregulation of angiogenesis, an essential process for the formation of new blood vessels following ischemia, and enhances vascular ageing (senescence), increasing the risk of amputation for patients with diabetes. Our laboratory has shown that the increased expression of protein tyrosine phosphatase SHP-1 in the ischemic muscle of diabetic mice was associated with higher phosphatase activity in the endothelial cells (EC) exposed to high concentrations of glucose. Our objective was to evaluate the role of SHP-1 in the regulation of the angiogenic process and senescence in the EC and ischemic muscle of diabetic mice. Diabetic (DM) and non-diabetic (NDM) mice with or without EC-specific deletion of SHP-1 underwent femoral artery ligation. Blood reperfusion was measured over a 4-week period using Doppler laser imaging and muscles were harvested for protein analysis. Histological staining was also performed in the ischemic muscle of all groups of mice. In vitro, EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations and placed under a hypoxic environment (1% O2) in the presence or absence of the angiogenic factor VEGF (10 ng/mL) with or without overexpression of dominant negative of SHP-1. Four weeks after surgery, blood reperfusion, limb function (distance traveled in a running wheel) and formation of new collateral vessels in ischemic muscle were significantly reduced in DM mice compared to NDM mice. These effects of diabetes were prevented by the EC-specific deletion of SHP-1. In vitro, the use of a dominant negative SHP-1 reversed HG-induced inhibition of VEGF actions in EC by restoring phosphorylation of VEGFR-2 and Akt. Meanwhile, inhibition of SHP-1 prevented the increased expression of p21 and β-galactosidase as well as the reduction of Nrf2, three senescence markers, caused by HG exposure. In conclusion, EC-specific deletion of SHP-1 prevented the effects of diabetes on senescence and angiogenesis leading to improved blood reperfusion and limb function in diabetic mice.","Le diabète cause une dérégulation de l’angiogenèse, un processus essentiel à la formation de nouveaux vaisseaux suite une ischémie et augmente le vieillissement vasculaire (sénescence) contribuant à un risque élevé d’amputation. Notre laboratoire a montré une augmentation de l’expression de la protéine tyrosine phosphatase SHP-1 dans le muscle ischémique de souris diabétiques, qui se traduit par une augmentation de son activité phosphatase dans les cellules endothéliales (CE) exposées à une concentration élevée de glucose. Notre objectif était d’évaluer le rôle de SHP-1 dans la régulation du processus angiogénique et de la sénescence dans les CE et du muscle ischémique diabétique. Des souris diabétiques (DM) et non-diabétiques (NDM) avec ou sans délétion de SHP-1 spécifique aux CEs ont subi une ligature de l’artère fémorale. La reperfusion sanguine a été mesurée sur une période de 4 semaines à l’aide d’un laser Doppler et les muscles ont été récoltés pour analyses protéiques. Des marquages histologiques ont également été effectués dans les muscles ischémiques. In vitro, des CE ont été exposées à des concentrations normales (5.6 mM; NG) ou élevées (25 mM; HG) de glucose et mises en condition d’hypoxie (1% d’O2) en présence ou non du facteur angiogénique VEGF (10 ng/mL) avec ou sans surexpression d’un adénovirus dominant négatif de SHP-1. Quatre semaines suivant la chirurgie, la reperfusion sanguine, la fonction motrice (distance parcourue en cage à roue) et la formation de nouveaux vaisseaux collatéraux dans le muscle ischémique étaient réduites significativement chez les souris DM comparées aux souris NDM, des effets rétablis par la délétion spécifique dans les CE de SHP-1. In vitro, l’utilisation d’un dominant négatif de SHP-1 a renversé les effets néfastes du HG sur l’angiogenèse des CE induits par le VEGF en rétablissant la phosphorylation du récepteur VEGFR-2 ainsi que Akt. En parallèle, l’inhibition de SHP-1 a empêché l’augmentation de l’expression de p21 et de la bêta-galactosidase ainsi que la réduction de Nrf2, tous des marqueurs de sénescence, causées par l’exposition au HG. En conclusion, la délétion spécifique aux cellules endothéliales de SHP-1 a permis de renverser les effets du diabète sur la sénescence et l’angiogenèse permettant d’améliorer la reperfusion sanguine et la fonction motrice chez les souris diabétiques."],"dc:identifier.uri":["http://hdl.handle.net/11143/20439"],"dc:language.iso":["fr"],"dc:publisher":["Université de Sherbrooke"],"dc:subject":["Maladie des artères périphériques","Diabète","Sénescence","Angiogenèse","SHP-1","VEGF","p21","Peripheral arterial disease","Diabetes","Senescence","Angiogenesis"],"dc:title":["Délétion endothéliale de SHP-1 prévient la sénescence et rétablit l’angiogenèse des cellules endothéliales vasculaires en condition de diabète"],"dc:type":["Mémoire de maîtrise"],"thesis:degree_discipline":["Physiologie"],"thesis:degree_level":["Maîtrise"],"thesis:degree_name":["M. Sc."],"thesis:institution_name":["Faculté de médecine et des sciences de la santé"]},"updated_at":"2026-07-27T21:07:32Z"}