High salt intake as a risk factor for endothelial dysfunction and coronary vascular disease

It is well accepted that high dietary salt intake is linked to development of hypertension, left ventricular hypetrophy,  coronary heart disease and stroke. Interestingly, high salt diet can alter vascular reactivity even in normotensive subjects, thus presenting an independent risk factor for vascular disease. High salt diet affects macro and microvascular function by increasing vascular oxidative stress, by decreasing NO bioavailability / production and by altering many singnaling pathways involved in vascular reactivity. Increased oxidative stress is a consequence of disbalance of production and elimination of reactive oxygen species. Several studies demonstrated decreased expression or activity of vascular antioxidative enzymes such as superoxide dismutase and gluthatione peroxidase in high salt diet (1). Oxidative stress is related to increased endothelial cell activation, attraction of leukocytes and increased endothelial-leukocyte interaction, leading to low-grade inflammation (2), as a first step in development of atherosclerosis.

Endothelial dysfunction is in the core of disturbed microvascular reactivity. Upon significant efforts in last few decades, new potential molecular mechanisms that connect high salt intake, hypertension and vascular disease at the level of endothelial cells emerged. 

Recently, special interest is evoked by the role of endothelial glycocalyx (eGC) in endothelial dysfunction. eGC surfaces the endothelial cells and is composed of proteoglycans, glycosaminoglycans (GAGs) and adsorbed plasma proteins (3). GAGs can serve as a buffer during sodium dietary depletion or excess and store Na+ in osmotically inactive form, and dysfunction of eGC is linked to sodium sensitivity (3). Accumulation of Na+ in tissue due to eGC dysfunction lead to macrophage infiltration, vascular inflammation and changes in local renin-angiotensin-aldosteron system. Inflammation is linked to pathological activation of coagulation and formation of neutrophil extracellular trap (NETosis) (3). In addition, eGC may contribute to impaired shear stress induced production of nitric oxide (NO) thus altering vascular relaxation mechanims.  Furthermore, perturbations of eGC lead to dysregulation of the coagulation system which is involved in pathogenesis of coronary heart disease (4). Taken together, altered molecular mechanisms at the level of eGC may underly endothelial dysfunction in high salt diet and hypertension.

In an effort to perform systematic mollecular characterization of eGS and EC in a mice model of high salt - induced hypertension (HSH), Vinaiphat et al. utilized novel technique, a differential systemic decellularization in vivo approach (DISVIVO) (5), followed by proteome and functional analysis, as well as imaging and histopathological evaluation. This study for the first time unequivocally revealed considerable eGC derangement, affecting metabolism, contractility and mechano-transduction and coagulation cascade, among other. Importantly, the integrins associated with arterial wall inflammation and infiltration of CD68+ monocyte-macrophages were presented. Several eGC biomarkers were identified as altered by HSH, related to EC lipid metabolism and oxidation, vascular contractile apparatus and mechano-transduction (which play roles in cardiac muscle contraction or hypertrophic cardiomyopathy, indicating that extensive vascular remodeling occurs in HSH) and increased susceptibility to coagulation due to increased accumulation of plasminogen and plasmin inhibitor carboxypeptidase B2. HDH promoted outward hypertrophic remodeling and aorta stiffness and increased vascular permeability of multiple organs including lungs, kidney, and heart (but not brain and liver tissue) with macrophage infiltration (5). However, the limitation of the study by Vinaiphat et al. is that it is not possible to discern the effects of high salt intake per se on eGC, independently of effects induced by increase in blood pressure. It would be valuable to conduct similar study in models on increased dietary salt intake in shorter duration, with lower amount of NaCl (i.e.  <8% as it was used) to elucidate the effects of NaCl intake only.

In conclusion, considering that no specific biochemical markers of microvascular function are available, identification of an array of molecules related to endothelial dysfunction, such as in work by Vinaiphat et al. could be a step further to achieve this goal.