Endothelial ageing: molecular mechanisms and functional significance

Le résumé fourni par la source

Cardiovascular mortality is closely linked to disturbances of the tightly regulated balance between endothelium-mediated vasodilatation and vasoconstriction, inhibition and proliferation of vascular smooth muscle, thrombogenesis and fibrinolysis, inflammation and cellular adhesion. The mechanisms of endothelial cell dysfunction in many disease conditions, such as hypertension, dyslipidaemia and diabetes, indicate a common pathway involving increased oxidative stress and a reduced availability of nitric oxide. Often cardiovascular diseases develop in later life, and the association between ageing and unfavourable risk factors, such as high body mass index, smoking and lack of physical activity, makes it difficult to assess how endothelial cell ageing per se contributes to cardiovascular impairment. The following papers were presented at a symposium entitled Endothelial Ageing: Molecular Mechanisms and Functional Significance held during the main meeting of The Physiological Society at the University of Cambridge on the 16th of July 2008, designed to elucidate this issue. Jorge Erusalimsky (Erusalimsky & Skene, 2009) addresses the lifespan processes whereby endothelial cells proliferate and reach senescence, exploring the notion that endothelial ageing is accelerated through telomere shortening and damage. Evidence is presented that vascular endothelial growth factor-A and high levels of nitric oxide, acting to alter the redox environment, are implicated in modulation of telomerase and hence cell senescence. In the paper by Berndt van der Loo (van der Loo et al. 2009), age-related mitochondrial accumulation of reactive oxygen species and the potential for cellular antioxidants (superoxide dismutases) or sirtuins (NAD+-dependent protein deacetylases) to protect against this are discussed in the context of chronic exposure to reactive oxygen species triggering endothelial and vascular dysfunction. The functional consequences of human endothelial ageing throughout life, particularly in the microvasculature, are discussed by Phillip Gates and colleagues (Gates et al. 2009). Impairment of endothelial vasodilator capacity is evident even in babies and children exposed to certain cardiovascular risk factors, and in adults, reduced microvessel function as a result of the interaction of biological and lifestyle factors with normal ageing processes acts as an early prognostic feature of cardiovascular and metabolic disease. From a clinical perspective, Stefano Taddei and colleagues (Versari et al. 2009) observe decreased macro- and microcirculatory endothelium-dependent dilatation during healthy ageing, linked to compromised availability of nitric oxide. The association of endothelial dysfunction with subclinical atherosclerotic disease and the reduced cardiovascular risk when dysfunction is ameliorated by therapeutic intervention serve to highlight the need for strategies to protect against endothelial ageing per se, in addition to risk factor modification. The insight into cellular mechanisms afforded by these papers raises the prospect of new approaches to achieve this.

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