C.F. Sanchez-Ferrer1, C. Peiro1, L. Rodriguez-Mañas2
1Dept. Farmacologia, Fac. Medicina, Universidad Autonoma, Madrid, Spain, 2Servicio de Geriatria, Hospital Universitario de Getafe, Madrid, Spain
Vascular endothelial dysfunction is a crucial event in the development of many vasculopathies but is also occurring during the aging process. It has been proposed that vascular disease and vascular aging are “partners”, each contributing with specific components to what is referred to “vasculopathy”. If so, it is important to determine whether those vascular diseases (including hypertension, atherosclerosis, or diabetic vasculopathy) known to produce endothelial dysfunction, oxidative stress, and inflammation, are exacerbating the same mechanisms activated in vascular aging. Investigating the underlying mechanisms of endothelial dysfunction in the vasculature of subjects between 22-91 years without cardiovascular disease, we first observed both in vivo and in vitro an analogous impairment of the endothelium-dependent relaxations. Afterwards, we demonstrated in vitro the presence of a COX-derived vasoconstrictor in vessels from aged subjects, although the expression of both COX-1 and COX-2 was not altered. Furthermore, evidence of superoxide anions production was obtained in aged vessels, which appeared to be produced by an enhanced NADPH oxidase and by “uncoupling” NOS. Interestingly, clear evidence of an age-related vascular inflammation was also observed, which was related to the development of endothelial dysfunction. Indeed, aged microvessels showed peroxynitrite formation, enhancement of iNOS expression, and NF-_B activation. In addition, the pharmacological interference of either oxidative or inflammatory mechanisms induced similar improvements of the age-related endothelial dysfunction. To our knowledge, this is the first direct evidence in the human vasculature linking the gradual impairment of the endothelial function associated to age with vascular wall inflammation in addition to oxidative stress.