The importance of endothelin-1 for microvascular dysfunction in diabetes

Abstract

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ETA receptor antagonists are discussed.

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

“…[14] Produced in excess, ET-1 triggers a series of critical events comprising inflammation, oxidative stress, fibrosis, and cellular phenotypic alterations of the vascular resident cells and infiltrated immune cells which converges to vascular dysfunction and ultimately cardiovascular diseases and downstream complications. [25,26] Thus far, the pathophysiological processes involved in the induction of ET-1 are insufficiently elucidated. Several lines of evidence indicate that the vascular inflammation-and growthpromoting transcription factors NF-kB and AP-1 are also important regulators of ET-1 expression.…”

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1

“…Diminished production of NO and aggravated release of ET1 are thought to be key initiators of endothelial injury (Little et al 2008. oxLDL causes abnormalities in endothelial function by decreasing eNOS activity in ECs (Cominacini et al 2001, Zhou et al 2013) and further promotes a proatherosclerotic 'vicious circle' by augmenting ET1 release and superoxide anion formation in the vessel wall (Morawietz et al 2002, Kalani 2008. It is therefore possible that ET1 contributes to endothelial dysfunction both directly, through its vasoconstrictor effects, and indirectly, through inhibition of NO production.…”

Evaluation of biochemical and clinical markers of endothelial dysfunction and their correlation with urinary albumin excretion in patients with type 1 diabetes mellitus

“…In the early phase of ED, an imbalance between endothelium-derived vasodilator and vasoconstrictor substances develops (7). Endothelin-1 (ET-1) is not only one of the most potent vasoconstrictors but it also has pro-inflammatory and profibrotic effects, which may contribute to the pathogenesis of nephropathy.…”