This review provides a comprehensive overview of the molecular mechanisms underlying diabetic macroangiopathy, a complication commonly seen in individuals with diabetes. |
Type 2 diabetes mellitus accelerates atherosclerosis and an increased risk of thrombotic vascular events due to dyslipidemia, endothelial dysfunction, poor fibrinolytic balance, and irregular blood flow. |
Tight glycemic management, normal lipid profiles, frequent physical exercise, a healthy lifestyle, and pharmaceutical therapies are useful tools to avoid and treat diabetic macroangiopathy. |
Introduction
Pathophysiology of Macrovascular Angiopathy in People with Diabetes
Hyperglycemia
Lipids and Lipoproteins
Insulin Resistance
Oxidative Stress
Activation of PKC
Growth Factors and Cytokines
Diabetes and Vascular Injury: Mechanism and Complications
Coronary Heart Disease
Cardiomyopathy
Arrhythmias and Sudden Death
Cerebrovascular Disease
Peripheral Vascular (Arterial) Disease
Neovascularization: Mechanism, Structural, and Functional Characteristics
Role of the Immune System in Vascular Wound Healing
Role of MicroRNA in Wound Healing
Current Developments in Diabetic Vascular Angiopathy Treatments
Diabetic complications | Medication | Mechanism of action |
---|---|---|
Hypertension | ACE inhibitors: fosinopril, moexipril, quinapril, ramipril, captopril, enalapril, and benazepril | Increase bradykinin levels by inhibiting the production of AII. As a result, vasoconstriction is reduced, salt and water retention are reduced, and vasodilation (via bradykinin) is increased |
Beta-blockers: propranolol, metoprolol, nadolol, carteolol, atenolol, bisoprolol, acebutolol, penbutolol, labetalol, carvedilol Calcium channel blockers: verapamil, diltiazem, dihydropyridine Diuretics: thiazide diuretics, loop diuretics, K-sparing diuretics | AII receptor (type 1) is inhibited competitively. Loop diuretics and potassium-sparing diuretics have a more specific effect on AII action but have little or no effect on bradykinin production or metabolism. Lower blood pressure via emptying body salt stores results in a decrease in total blood volume and CO; initially, peripheral vascular resistance increases, but decreases when CO returns to normal (6–8 weeks) | |
Hyperglycemia and insulin resistance | Biguanides: metformin | Suspend polysaccharide absorption, and slow down postprandial glucose excursions |
Sulfonyl ureas: chlorpropamide, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, and tolbutamide Alpha-glucosidase inhibitors: acarbose | Insulin secretagogues | |
Sulfonyl urea-like agents: repaglinide | Insulin sensitizers promote glucose absorption in adipose and skeletal muscle tissues | |
Thiazolidinediones: pioglitazone, rosiglitazone | ||
Insulin | Increases peripheral glucose consumption while decreasing hepatic glucose output | |
Dyslipidemia | Statins: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin | Improve lipid profile and reduce your risk of atherosclerosis. Lower LDL-C, increase TC/HDL-C, and decrease apolipoprotein |
Fibric acid derivatives: bezafibrate, fenofibrate, gemfibrozil | Improve your lipid profile and reduce your risk of atherosclerosis. drop TGs, boost HDL-C, drop TC/HDL-C, and shift LDL particles from smaller to larger | |
Platelet activation and aggregation | Aspirin | Antiplatelet effect |
Clopidogrel | Irreversible ADP receptor blockage on platelet cell membranes | |
Ticlopidine |
Hyperbaric Oxygen Treatment
Therapies with VEGF and PDGF
Therapeutics | Molecular target | Mechanism | References |
---|---|---|---|
Azelnidipine | eNOS | Upregulates eNOS and accelerates healing by stimulating NO production | [157] |
Pentoxifylline | MMPs, TIMP-1 | Lowers expression of MMPs and enhances TIMP-1 | [158] |
Erythropoietin | VEGF | Stimulates VEGF and hydroxyproline | [159] |
Atorvastatin gel | Collagen | Increases collagen regeneration and epithelization | [160] |
Substance P | IL-8 | Induces leukocytes and macrophages | [161] |
Deferoxamine | HIF-1α, SDF-1α, VEGF | Upregulates HIF-1α to stimulate neovascularization | [162] |
Propranolol | VEGF, TGFβ, IL-8, MMP-9 | Increases cell proliferation, collagen deposition, and blood vessel density, and reduces inflammatory cells | [163] |
Novel nano-insulin | IL-6, IL-10, TNFα | Promote faster wound healing, and balance between IL-6, IL-10, and TNFα | [164] |
Glucophage | MMP-9 | Stimulates collagen-1 and epithelization to improve healing | [165] |
GW50516 | Peroxisome proliferative-activated receptor | Reduces ROS activity | [166] |
Adenine | AMP-activated protein kinase | Activates PPARδ, and reduce AGE receptors | [167] |
MK0626 | HIF-1α/SDF-1 | Induces healing, angiogenesis, and endogenous progenitor cells | [168] |
Bee venom | Nrf2, Ang-1 and Ang-2 signaling | Enhances collagen and the expression of BD-2, and reduces the Ang-1 and Nrf-2 signaling | [169] |
Adiponectin | TGFβ | Regulates the expression of TGFβ to restrain proliferation and differentiation | [170] |
Neurotensin | TNFα, IL-1β | Improves healing by reducing inflammation, and inducing fibroblast migration | [171] |
MMP inhibitor | MMP, TIMP | Blocks MM-9 to induce healing | [172] |
Hyaluronic acid | TGFβ | Accelerates healing by inducing skin remodeling protein, TGFβ, and transglutaminase II | [173] |
Angiopoietin-like receptor | Nitric oxide | Improves angiogenesis by inducing NO production | [174] |
PDGF, TGFα | PDGF and TGFα | Stimulates fibroblast mitogen and keratinocytes | [175] |