Redox Stress Defines the Small Artery Vasculopathy of Hypertension

Abstract

While convincing experimental evidence demonstrates the importance of vascular reactive oxygen and nitrogen species (RONS), oxidative stress and perturbed redox signaling as causative processes in the vasculopathy of hypertension, this has not translated to the clinic. We discuss this bench-to-bedside disparity and the urgency to progress vascular redox pathobiology from experimental models to patients by studying disease-relevant human tissues. It is only through such approaches that the unambiguous role of vascular redox stress will be defined so that mechanism-based therapies in a personalized and precise manner can be developed to prevent, slow or reverse progression of small vessel disorders and consequent hypertension.

Oxidative Stress: A Unifying Paradigm in Hypertension

“…[58][59][60][61] Although experimental data support an etiologic role for oxidative stress in the development of hypertension, there is still no confirmation that oxidative stress is a primary cause of hypertension in humans. Reasons for this are complex, as we have previously highlighted, 62 and relate in large part to 1) lack of sensitive and specific assays that can accurately assess redox state in the clinical setting, 2) paucity of mechanistic studies in disease-appropriate human tissue, and 3) absence of pharmacologic agents that specifically target Nox isoforms or ROS that could be used in patients. Nevertheless, there is clear evidence that ROS production is increased in patients with essential hypertension, renovascular hypertension, malignant hypertension, salt-sensitive hypertension, cyclosporine-induced hypertension, and preeclampsia.…”

“…Impaired endothelium-dependent vasorelaxation, increased vasoconstriction, vascular remodelling and inflammation, reduced distensibility, and increased stiffness are characteristic features of small and large arteries in hypertension and constitute the vascular phenotype, or "vasculopathy," of hypertension. 62,88,89 Some of these vascular changes occur with physiologic aging, but in hypertension and diabetes the processes are accelerated, leading to "premature vascular aging," a process that is highly redox sensitive. 90,91 These phenomena are dynamic and involve functional (contraction-relaxation) and structural changes (remodelling) that occur at different phases during development of hypertension.…”

“…93,94 Common to many of these processes is oxidative stress and activation of redoxsensitive signalling pathways. 34,62,90 Ang II and ET-1…”

MicroRNA-214-3p in the Kidney Contributes to the Development of Hypertension

“…Analysis of miRNA abundance in body fluids could be done in large numbers of subjects and generate useful biomarkers, although it might be difficult to interpret the mechanistic relevance of body fluid miRNAs to hypertension as we recently discussed. 58 The role of sequence variations in complex, polygenic traits such as hypertension depends highly on genomic, environmental, and cellular context. 34,57,59 Despite the inevitable limitations of the human study, the two-pronged approach nominated miR-214 as one of the top-ranked miRNAs in human hypertension, which warrants further investigation.…”

Microvascular function and oxidative stress in adult individuals with early onset of cardiovascular disease

“…As the effects of radical oxygen species (ROS) on vascular tone is dependent upon the concentration and type of species, as well as on the type of vascular beds and various experimental conditions 39 , it is possible that these effects were not visible in our specific setup. Indeed, it has been proposed that there is a lack of sensitive methods to accurately evaluate the oxidative stress in the human cardiovascular system, especially when it comes to establishing the role redox stress in the small artery vasculopathy of human hypertension 40 .…”