Endothelial dysfunction in diabetes: multiple targets for treatment

Abstract

Robert Furchgott's discovery of the obligatory role that the endothelium plays in the regulation of vascular tone has proved to be a major advance in terms of our understanding of the cellular basis of diabetic vascular disease. Endothelial dysfunction, as defined by a reduction in the vasodilatation response to an endothelium-dependent vasodilator (such as acetylcholine) or to flow-mediated vasodilatation, is an early indicator for the development of the micro- and macroangipathy that is associated with diabetes. In diabetes, hyperglycaemia plays a key role in the initiation and development of endothelial dysfunction; however, the cellular mechanisms involved as well as the importance of dyslipidaemia and co-morbidities such as hypertension and obesity remain incompletely understood. In this review, we discuss the mechanisms whereby hyperglycaemia, oxidative stress and dyslipidaemia can alter endothelial function and highlight their effects on endothelial nitric oxide synthase (eNOS), the endothelium-dependent hyperpolarising factor (EDHF) pathway(s), as well as on the role of endothelium-derived contracting factors (EDCFs) and adipocyte-derived vasoactive factors such as adipose-derived relaxing factor (ADRF).

Role of impaired endothelial cell Ca2+signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy

“…There is experimental and clinical evidence for the presence of impaired endothelium-dependent vasodilation in various vascular beds of animal models of diabetes or in humans with type 1 and type 2 diabetes (18,20,22,27). The results of the present study clearly demonstrate the significant attenuation of ACh-induced vasodilation of small radial uteroplacental arteries from diabetic pregnant rats.…”

“…The colocalization of the endothelial ER and IK Ca channels in myoendothelial projections of the mesenteric vasculature has been recently reported (48 Hyperglycemia is considered as a major causal factor of diabetes-associated endothelial dysfunction in animals and humans (20,22,30,31). However, experimental studies of hyperglycemia-evoked vascular effects have produced conflicting results.…”

“…These data suggest that diabetes may modulate Ca 2ϩ sensitivity/ activation and/or cellular trafficking of SK Ca /IK Ca channels in blood vessels independently of channel expression. In addition, impaired expression and/or function of connexins of myoendothelial gap junctions may play a role in the reduced EDHFmediated responses of uterine arteries in diabetic pregnancy (22). Further studies are needed to clarify the contribution of SK Ca /IK Ca channels and connexins to endothelial dysfunction in the maternal uterine vasculature of diabetic rats.…”

Inhibition of Protein Kinase C β Ameliorates Impaired Angiogenesis in Type I Diabetic Mice Complicating Myocardial Infarction

“…31 The generation of NO is regulated by both the absolute level of eNOS protein and protein kinase B (Akt)-mediated phosphorylation of the eNOS level. 32 As mentioned earlier, the activation of PKC β isoforms inhibits phosphorylation of eNOS via a PI3K/Akt pathway that is stimulated by insulin. Furthermore, VEGF itself has effects on the phosphorylation of eNOS through this same pathway.…”

Impairment of IKCachannels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy

“…Endothelial dysfunction is considered a key mechanism of diabetic vascular disease, as evidenced by impaired endothelium-dependent vasodilation in various vascular beds of diabetic animals and humans (12)(13)(14)20). Previously, we demonstrated that EDHF-mediated uterine vasodilation was severely reduced by diabetic pregnancy, indicating that an impairment of the EDHF system importantly contributes to uteroplacental endothelial dysfunction (24).…”