Diabetes Impaired Ischemia-Induced PDGF (Platelet-Derived Growth Factor) Signaling Actions and Vessel Formation Through the Activation of Scr Homology 2-Containing Phosphatase-1

Autor: Elizabeth Boisvert, Valérie Breton, Andréanne Guay, Clément Mercier, Farah Lizotte, Pedro Geraldes, Stéphanie Robillard, Martin Paré, Tristan Brazeau, Jérémy Lamoureux, Marc-Antoine Despatis
Rok vydání: 2021
Předmět:
Blood Glucose
Male
0301 basic medicine
Platelet-derived growth factor
medicine.medical_treatment
030204 cardiovascular system & hematology
Muscle
Smooth
Vascular
chemistry.chemical_compound
0302 clinical medicine
Cell Movement
Ischemia
Cells
Cultured
Mice
Knockout
Platelet-Derived Growth Factor
biology
Protein Tyrosine Phosphatase
Non-Receptor Type 6
Cell Hypoxia
Hindlimb
medicine.symptom
Cardiology and Cardiovascular Medicine
Platelet-derived growth factor receptor
Signal Transduction
medicine.medical_specialty
Myocytes
Smooth Muscle
Neovascularization
Physiologic
Diabetes Mellitus
Experimental
03 medical and health sciences
Growth factor receptor
Downregulation and upregulation
Diabetes mellitus
Internal medicine
medicine
Animals
Humans
Cell Proliferation
business.industry
Growth factor
Hypoxia (medical)
medicine.disease
Enzyme Activation
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
chemistry
Case-Control Studies
biology.protein
Angiogenesis Inducing Agents
Cattle
business
Diabetic Angiopathies
Zdroj: Arteriosclerosis, Thrombosis, and Vascular Biology. 41:2469-2482
ISSN: 1524-4636
1079-5642
DOI: 10.1161/atvbaha.121.316638
Popis: Objective: Critical limb ischemia is a major complication of diabetes characterized by insufficient collateral vessel development and proper growth factor signaling unresponsiveness. Although mainly deactivated by hypoxia, phosphatases are important players in the deregulation of proangiogenetic pathways. Previously, SHP-1 (Scr homology 2-containing phosphatase-1) was found to be associated with the downregulation of growth factor actions in the diabetic muscle. Thus, we aimed to gain further understanding of the impact of SHP-1 on smooth muscle cell (SMC) function under hypoxic and diabetic conditions. Approach and Results: Despite being inactivated under hypoxic conditions, high glucose level exposure sustained SHP-1 phosphatase activity in SMC and increased its interaction with PDGFR (platelet-derived growth factor receptor)-β, thus reducing PDGF proangiogenic actions. Overexpression of an inactive form of SHP-1 fully restored PDGF-induced proliferation, migration, and signaling pathways in SMC exposed to high glucose and hypoxia. Nondiabetic and diabetic mice with deletion of SHP-1 specifically in SMC were generated. Ligation of the femoral artery was performed, and blood flow was measured for 4 weeks. Blood flow reperfusion, vascular density and maturation, and limb survival were all improved while vascular apoptosis was attenuated in diabetic SMC-specific SHP-1 null mice as compared to diabetic mice. Conclusions: Diabetes and high glucose level exposure maintained SHP-1 activity preventing hypoxia-induced PDGF actions in SMC. Specific deletion of SHP-1 in SMC partially restored blood flow reperfusion in the diabetic ischemic limb. Therefore, local modulation of SHP-1 activity in SMC could represent a potential therapeutic avenue to improve the proangiogenic properties of SMC under ischemia and diabetes.
Databáze: OpenAIRE
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