Hypertension (HTN) is one of the most frequent disease and is of greatest concern in Western countries.HTN is often associated with overweight, kidney, heart and endocrine system disease. Vasculardisorders, associated with HTN induced by erythropoietin (r-HuEPO) treatment in chronic kidneydisease or in case of disruption of the renin-angiotensin-aldosterone system (RAAS), associated increasein arterial stiffness, endothelial dysfunction, unbalanced endothelin-1/nitric oxide ratio (ET-1/NO) andinflammation. Vascular inflammation contributes to the pathophysiology of hypertension by increasingoxidative stress and activation of immune cells. Several studies have suggested that the immune systemis involved in the development of cardiovascular disease. However, the role of regulatory T cells (Treg)in HTN and other forms of cardiovascular diseases remains largely unknown. In addition, most of thestudies have shown that hypertension induced by r-HuEPO is related to endothelial dysfunction and theratio (ET-1/NO). The exact mechanisms remain to be identified. Several studies have shown thatphysical exercise prevents HTN in patients or animal models. The aim of the first part of this work is tostudy the impact of shear stress and exercise on HTN and vascular disorders induced by r-HuEPO, in thepresence of an endothelial imbalance (ET-1/NO). This was carried out in three settings: in vitro (culturecells), ex vivo (mesenteric arteries) and in vivo (transgenic mice overexpressing ET-1 in endothelialcells). Our results show that the association L-NAME/r-HuEPO is responsible for a significant decreasein intravascular diameter, in response to elevated intravascular flow resulting in a flow-dependentvasoconstriction and increased corresponding shear stress (more than 25 dyn/cm2). Bosentan (a nonselectiveantagonist of ET-1 receptors) inhibits flow-dependent vasoconstriction induced by thecombination L-NAME/rHu-EPO without correcting vasodilation. Treatment of ET-1 transgenic micewith r-HuEPO increases systolic blood pressure, ET-1 plasma concentration, oxidative stress, infiltrationof aortic monocytes and macrophages (MOMA-2), pro-inflammatory cytokines levels INF-γ, TNF-α andIL-6 and exacerbate endothelial dysfunction. Exercise prevents all the deleterious effects of r-HuEPO. Itis also noteworthy that exercise increases the number of Foxp3-positive cells in the spleen and renalcortex. Then, the second aim of our study was to test the effect of adoptive transfer of Treg cells on HTNand vascular disorders induced in mice treated with angiotensin II (Ang II) or aldosterone (Aldo). Ourresults show that adoptive transfer of Treg prevents Ang II induced hypertension, endothelialdysfunction, prevents stiffness of mesenteric arteries, decreases oxidative stress and plasma levels ofpro-inflammatory cytokines (IFN-γ, TNF-α and IL-6) and the aortic and renal infiltration ofmacrophages. Adoptive transfer of Treg prevents the increase in systolic blood pressure induced byAldo, prevents impaired endothelium-dependent vasodilatation and hypertrophic remodelling ofmesenteric arteries, decreases oxidative stress and infiltration of inflammatory immune cells. Theadoptive transfer of T effectors cells (Teff) exacerbates the majority of the Aldo effects. Our resultsjustify, on one hand, the importance of exercise as a preventive tool for hypertension induced by r-HuEPO, and on the other hand, highlight the role of Treg as an essential component in the modulation ofhypertension and cardiovascular disorders.
Recombinant human erythropoietin and renin-angiotensin aldosterone system induced hypertension and vascular disease : Effect of exercise and T regulatory cells