Uric acid is the final product of purine metabolism, and its increased serum levels have been directly involved in the pathogenesis and natural history of hypertension. The relationship between elevated uric acid and hypertension has been proven in both animals and humans, and its relevance is already evident in childhood and adolescent population. The mechanism responsible for blood pressure increase in hyperuricemic subjects is implicating both oxidative stress and intracellular urate activity with a primary involvement of XOR (xanthine-oxidoreductase activity). An increase in the relative risk of hypertension has been confirmed by genetic data and by large meta-analyses of epidemiological data. The effects of urate-lowering treatment on blood pressure control in patients with elevated serum uric acid has been investigated in a small number of reliable studies with a large heterogeneity of patient populations and study designs. However, 2 large meta-analyses suggest a significant effect of urate-lowering treatment on blood pressure, thus confirming the significant relationship between high serum urate and blood pressure. The future research should be focused on a more appropriate identification of patients with cardiovascular hyperuricemia by considering the correct cardiovascular threshold of serum urate, the time-course of uricemia fluctuations, and the identification of reliable markers of urate overproduction that could significantly clarify the clinical and therapeutic implications of the interaction between serum uric acid and hypertension.

The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

We assessed the impact of vascular and perivascular tumour necrosis factor-alpha (TNF-α) on the endothelin (ET)-1/nitric oxide (NO) system and the molecular pathways involved in small arteries from visceral fat of obese patients (Obese) and Controls. Isolated small arteries from 16 Obese and 14 Controls were evaluated on a pressurized micromyograph. Endogenous ET-1 activity was assessed by the ET_A blocker BQ-123. TNF-α and NO were tested by anti-TNF-α infliximab (IFX) and N^ω-nitro-l-arginine methylester (L-NAME). Gene and protein expression of TNF-α, ET-1, ET_A, and ET_B receptors were determined by RT-PCR and IHC on arterial wall and in isolated adipocytes. Obese showed a blunted L-NAME-induced vasoconstriction, which was potentiated by IFX, and an increased relaxation to BQ-123, unaffected by L-NAME but attenuated by IFX. Perivascular adipose tissue (PVAT) removal reversed these effects. Obese showed intravascular superoxide excess, which was decreased by apocynin (NAD(P)H oxidase inhibitor), L-NAME, and BQ-123 incubations, and abolished by IFX. An increased vascular expression of ET-1, ET_A, and ET_B receptors, and higher vascular/perivascular TNF-α and TNF-α receptor expression were also detected. The arterial expression and phosphorylation of c-Jun N-terminal kinase (JNK) were higher in Obese vs. Controls, and downregulated by IFX. In small arteries of Obese, PVAT-derived TNF-α excess, and an increased vascular expression of ET-1 and ET_A receptor, contribute to the ET-1/NO system imbalance, by impairing tonic NO release. Reactive oxygen species excess, via NAD(P)H oxidase activation, induces the endothelial nitric oxide synthase uncoupling, which in turn generates superoxide and impairs NO production. The up-regulated JNK pathway represents a crucial molecular signalling involved in this process.