Effects of Sex Differences on the myeloid-endothelin system and their implications for blood pressure control

Abstract

High blood pressure or hypertension is a common clinical condition affecting 25% of the UK adult population. It is a major risk factor for myocardial infarction, cerebral infarction, dementia, heart failure, kidney failure and retinopathy. Despite a broad range of treatment options, the cause of hypertension remains unknown, so patients cannot be easily identified before developing hypertension, nor can therapy be stratified to the cause of their increased blood pressure. The kidneys, heart, brain, immune system and vasculature all contribute to blood pressure. Recent studies have linked macrophages, an important cell type in the innate system, to the endothelin-1 (ET-1), a principal regulator of arterial tone and that the interaction affects blood pressure control. ET-1 is a vasoactive peptide that acts via two G-protein coupled receptors, ETA and ETB receptor, to induce vasoconstriction or vasodilation, respectively. The incidence of cardiovascular disease varies between men and women, with men more likely to develop it earlier. Additionally, women are more likely to develop autoimmunity, which increases their risk of cardiovascular disease. As such, this thesis hypothesised that the macrophage-endothelin system might vary between men and women, and this could be a possible explanation for the differences in risk of cardiovascular disease.

Initially, the dynamics of ET-1 uptake were observed using a fluorescently tagged ET-1 and microscopy in male C57BL/6 mice, and the ET system appears to affect cytokine release by macrophages. The use of the same probe indicated that only macrophages isolated from male mice could remove ET-1 in vitro, and this supported by a similar finding using an untagged ET-1. Furthermore, the ETB receptor gene, Ednrb, was shown to have higher expression in male macrophages compared to females, perhaps explaining the difference in ET-1 uptake. Next, sex differences in the macrophage-ET system were also observed in 129/Sv and FVB strains mouse strains. Finally, in vivo studies demonstrated that sex differences in the myeloid-ET system do not affect acute pressure regulation but significantly affect chronic blood pressure control. Female control mice had a greater response to the same dose of Ang II and a high salt diet than female LysMETB mice, where the macrophage ETB receptor has been depleted, and a higher response than male LysMETB mice. The differences could be explained by differences in circulating leucocytes and changes in vasoconstriction. There was no difference in renal injury, although there were differences in circulating ET-1. Differences in the macrophage-ET system may become physiologically relevant when immune function is altered, as can occur in cancer, cardiovascular disease and autoimmunity.