Deletion of AT2 Receptor Prevents SHP-1-Induced VEGF Inhibition and Improves Blood Flow Reperfusion in Diabetic Ischemic Hindlimb
| Autor: | Raphaël Beland, Farah Lizotte, Andréanne Guay, Stéphanie Robillard, Marc-André Breton, Marc-Antoine Despatis, Judith Paquin-Veillette, Pedro Geraldes |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Blood Glucose Male Vascular Endothelial Growth Factor A Angiotensin receptor Time Factors Angiogenesis 030204 cardiovascular system & hematology Renin-Angiotensin System chemistry.chemical_compound 0302 clinical medicine Cell Movement Ischemia Medicine Receptor Cells Cultured Mice Knockout Protein Tyrosine Phosphatase Non-Receptor Type 6 Hindlimb Vascular endothelial growth factor Endothelial stem cell Phenotype Cardiology and Cardiovascular Medicine Signal Transduction medicine.medical_specialty Genotype Neovascularization Physiologic Receptor Angiotensin Type 2 03 medical and health sciences Internal medicine Diabetes mellitus Diabetes Mellitus Animals Muscle Skeletal Cell Proliferation business.industry Endothelial Cells Recovery of Function medicine.disease Angiotensin II Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Receptors Vascular Endothelial Growth Factor chemistry Regional Blood Flow Cattle business Diabetic Angiopathies Gene Deletion |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 37(12) |
| ISSN: | 1524-4636 |
| Popis: | Objective— Ischemia caused by narrowing of femoral artery is a major cause of peripheral arterial disease and morbidity affecting patients with diabetes mellitus. We have previously reported that the inhibition of the angiogenic response to VEGF (vascular endothelial growth factor) in diabetic mice was associated with the increased expression of SHP-1 (SH2 domain–containing phosphatase 1), a protein that can be activated by the AT2 (angiotensin II type 2) receptor. Deletion of AT2 receptor has been shown to promote angiogenesis within the ischemic muscle. However, the relative impact of AT2 receptor in diabetic condition remains unknown. Approach and Results— Nondiabetic and diabetic AT2 null ( Atgr2 − /Y ) mice underwent femoral artery ligation after 2 months of diabetes mellitus. Blood perfusion was measured every week ≤4 weeks post-surgery. Expression of the VEGF, SHP-1, and renin–angiotensin pathways was evaluated. Blood flow in the ischemic muscle of diabetic Atgr2 − /Y mice recovered faster and ≤80% after 4 weeks compared with 51% recovery in diabetic control littermates. Diabetic Atgr2 − /Y had reduced apoptotic endothelial cells and elevated small vessel formation compared with diabetic Atgr2 +/Y mice, as well as increased SHP-1 expression and reduced VEGF receptor activity. In endothelial cells, high glucose levels and AT2 agonist treatment did not change SHP-1, VEGF, and VEGF receptor expression. However, the activity of SHP-1 and its association with the VEGF receptors were increased, causing inhibition of the VEGF action in endothelial cell proliferation and migration. Conclusions— Our results suggest that the deletion of AT2 receptor reduced SHP-1 activity and restored VEGF actions, leading to an increased blood flow reperfusion after ischemia in diabetes mellitus. |
| Databáze: | OpenAIRE |
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