Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?

Abstract

Twenty-five years ago, the discovery of endothelium-derived relaxing factor opened a door that revealed a new and exciting role for the endothelium in the regulation of blood flow and led to the discovery that nitric oxide (NO) multi-tasked as a novel cell-signalling molecule. During the next 25 years, our understanding of both the importance of the endothelium as well as NO has greatly expanded. No longer simply a barrier between the blood and vascular smooth muscle, the endothelium is now recognized as a complex tissue with heterogeneous properties. The endothelium is the source of not only NO but also numerous vasoactive molecules and signalling pathways, some of which are still not fully characterized such as the putative endothelium-derived relaxing factor. Dysfunction of the endothelium is a key risk factor for the development of macro- and microvascular disease and, by coincidence, the discovery that NO was generated in the endothelium corresponds approximately in time with the increased incidence of type 2 diabetes. Primarily linked to dietary and lifestyle changes, we are now facing a global pandemic of type 2 diabetes. Characterized by insulin resistance and hyperglycaemia, type 2 diabetes is increasingly being diagnosed in adolescents as well as children. Is there a link between dietary-related hyperglycaemic insults to the endothelium, blood flow changes, and the development of insulin resistance? This review explores the evidence for and against this hypothesis.

Glucose enhances expression of TRPC1 and calcium entry in endothelial cells

“…An extensive literature supports the link between hyperglycemia and endothelial dysfunction (3,47,48,52); however, the contribution of changes in Ca 2ϩ homeostasis to endothelial dysfunction remains controversial (49,50). In the present study, exposing BAECs to HG for 4, 24, or 72 h had no effect on the amplitude of Ca 2ϩ released from the intracellular store but increased the sustained Ca 2ϩ entry phase following the activation of the P2Y receptor after 24 and 72 h in HG.…”

Peripheral vascular function in spinal cord injury: a systematic review

“…[102][103][104] It is now widely accepted that chronic constriction of the blood vessels, particularly at the level of the resistance vessels, results in locally damaging increases in blood flow velocity and turbulence that can increase shear stress, damage the endothelium and produce maladaptive remodeling of the vasculature. [105][106][107] Indeed, Rizzoni et al 108 reported that such structural alterations in the small arteries represent the most potent predictor for CVD in the hypertensive population. Less is known about the effects of intermittent or episodic hypertension per se.…”

Association of Abdominal Circumference with Serum Nitric Oxide Concentration in Healthy Population

“…Although studies indicating that a reduced endothelium-derived NOx concentration reflects the development of atherosclerotic disorders are numerous (1,7,24,25), we found no significant differences in adjusted means in relation to all the MS components but a low HDL-C concentration in men, which is consistent with a previous result obtained using the biomarker cyclic guanosine 3',5'-monophosphate (cGMP), a second messenger of NO, excreted in urine collected from a large population-based sample (26). Consequently, we did not treat these MS components as covariates in the ANCOVA analyses.…”

“…Nitric oxide (NO) plays important physiological roles in the endothelium (1), where free radical gas NO is synthesized from the amino acid l-arginine by endothelial constitutive NO synthase (eNOS, NOS3) and released (2). Endothelium-derived NO is a potent vasodilator as well as an inhibitor of platelet aggregation and adhesion (3,4), and is associated with the development of cardiovascular disease (CVD) in the presence of endothelial dysfunction (ED), which plays an early and prominent role in atherosclerotic plaque formation (5,6).…”