Endothelial dysfunction and vascular disease - a 30th anniversary update

Abstract

The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

Naringin ameliorates endothelial dysfunction in fructose-fed rats

“…Endothelial dysfunction is generally characterized by a decrease in endothelial dependent relaxation. The vascular endothelium plays a vital role in the regulation of basal vascular tone through the synthesis and release of several vasodilators including nitric oxide (NO), prostaglandin I 2 (PGI 2 ) and endothelium-derived hyperpolarizing factor (EDHF) (7). It has been reported that endothelium-derived NO is a predominant mediator of endothelial-dependent relaxation in aortae, and its bioavailability is impaired in several pathophysiological states such as hyperlipidemia, metabolic syndrome, diabetes and hypertension (35,36).…”

“…NO is generated from the conversion of L-arginine to L-citrulline by endothelial NO synthase (eNOS) and has a potent vasodilator, anti-inflammatory, and antithrombotic properties (6). Reduction of NO bioavailability, caused by reduced eNOS activity and/or accelerated NO degradation, results in impaired endothelium-dependent vasorelaxation, increased thrombus formation, and progressive atherogenesis (7). There is growing evidence that fructose fed animals exhibited impaired endothelium-dependent relaxation (8)(9)(10)(11) and decreased NO bioavailability (12)(13)(14).…”

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…Although NO is by far the best‐characterized endothelium‐derived relaxing factor, others, such as prostacyclin and hydrogen peroxide, and endothelium‐derived constricting factors (eg, prostanoids and endothelin‐1) contribute to endothelial‐dependent vasomotion 61. Unfortunately, their impact on endothelial function, the development of CAD, and especially the role of exercise training on their regulation is less studied and needs further investigation.…”

Is the neutrophil extracellular trap-driven microvascular inflammation essential for diabetes vasculopathy?

“…Although the molecular basis responsible for vasculopathy in diabetes mellitus has been widely investigated, the innate pathogenic mechanisms affected various phases at the early stage of the disease have remained yet poorly understood (Bhatta et al, 2016). Diabetes-induced vasculopathy may be attributable to hyperglycemia, lipotoxicity, neurohumoral dysregulation of vascular function, increased prolonged exposure to oxidative stress, reduced production and release of nitric oxide, lowgrade microvascular inflammation, pro-thrombotic state, reduced ability to repair endothelial damage by recruitment of endothelial precursors, development of asymptomatic atherosclerosis (Bhatta et al, 2016;Lehoux and Jones, 2015;Leong et al, 2016;Vanhoutte et al, 2015). Indeed, hyperglycemia leads to accumulation of advanced glycation end-products (AGEs) that transduces inflammatory and proliferative response through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways (Yamagishi et al, 2009).…”