The endothelium, a thin single sheet of endothelial cells, is a metabolically active layer that coats the inner surface of blood vessels and acts as an interface between the circulating blood and the vessel wall. The endothelium through the secretion of vasodilators and vasoconstrictors serves as a critical mediator of vascular homeostasis. During the development of the vascular system, it regulates cellular adhesion and vessel wall inflammation in addition to maintaining vasculogenesis and angiogenesis. A shift in the functions of the endothelium towards vasoconstriction, proinflammatory and prothrombic states characterise improper functioning of these cells, leading to endothelial dysfunction (ED), implicated in the pathogenesis of many diseases including diabetes. Major mechanisms of ED include the down-regulation of endothelial nitric oxide synthase levels, differential expression of vascular endothelial growth factor, endoplasmic reticulum stress, inflammatory pathways and oxidative stress. ED tends to be the initial event in macrovascular complications such as coronary artery disease, peripheral arterial disease, stroke and microvascular complications such as nephropathy, neuropathy and retinopathy. Numerous strategies have been developed to protect endothelial cells against various stimuli, of which the role of polyphenolic compounds in modulating the differentially regulated pathways and thus maintaining vascular homeostasis has been proven to be beneficial. This review addresses the factors stimulating ED in diabetes and the molecular mechanisms of natural polyphenol antioxidants in maintaining vascular homeostasis.
Keywords: 6; 7; 8-tetrahydro-L-biopterin; ADMA asymmetric dimethylarginine; AGE advanced glycation end products; AMPK AMP-activated protein kinase; BH4 (6R)-5; Cell signalling; Diabetes; EGCG epigallocatechin gallate; ER endoplasmic reticulum; ET-1 endothelin-1; Endothelial dysfunction; GLP-1 glucagon-like peptide-1; ICAM intracellular adhesion molecule; IRE1 inositol-requiring enzyme 1; IRS-1 insulin receptor substrate 1; MCP-1 monocyte chemoattractant protein-1; NOX NADPH oxidase; NO∙ nitric oxide; Nrf2 nuclear factor-E2-related factor 2; PKC protein kinase C; Polyphenols; ROS reactive oxygen species; SGLT2 sodium–glucose co-transporter 2; STZ streptozotocin; T1D type 1 diabetes; T2D type 2 diabetes; UPR unfolded protein responses; VCAM vascular cell adhesion molecule; VEGF vascular endothelial growth factor; XO xanthine oxidase; cGMP cyclic GMP; eNOS endothelial nitric oxide synthase.