Sex steroid hormones - roles in adaptive immunity and vascular pathology

Abstract

The prevalence of autoimmune diseases is higher in women than men, while for cardiovascular disease, there is a male predominance. The sexual dimorphism of autoimmune and cardiovascular diseases probably relates to a number of factors, e.g. difference in exposure to risk factors and response to therapy, together with the effects of sex steroid hormones on disease pathophysiology. The sex difference and the effect of sex steroid hormones sometimes coincide while sometimes not: male sex and testosterone protect from autoimmune disease while male sex is considered a risk factor for CVD although testosterone is atheroprotective. Owing to this, it is important to in detail understand the targets and mechanisms for the effects of sex steroid hormones in vascular pathology and adaptive immunity. This thesis aimed to 1) determine the role of catechol-O-methyltransferase (COMT) for the vasculo-protective actions of estradiol, 2) determine the role of the androgen receptor (AR) in the atheroprotection actions of testosterone, 3) investigate the role of the AR in neointimal hyperplasia, 4) determine the mechanisms and target cells for AR-mediated regulation of B cell homeostasis, and 5) determine the mechanisms and target cells for AR-mediated regulation of T cell homeostasis in mice. Concluding the results in this thesis, we found that testosterone exerts its inhibitory effect on B lymphopoiesis in males by targeting the AR in osteoblasts while the thymic epithelial cells are a target for AR-mediated inhibition of T lymphopoiesis. A distinct regulation of peripheral B and T cell homeostasis may involve non-hematopoietic spleen cells and inhibition of B cell activating factor (BAFF) production. Moreover, testosterone exerts atheroprotection through AR-dependent as well as AR-independent pathways. The AR also mediates protection from neointimal hyperplasia as a response to vascular injury, possibly through regulation of endothelial nitric oxide production leading to reduced proliferatory capacity of vascular smooth muscle cells. Lastly, the COMT enzyme is dispensable for vascular protection by estradiol in vivo. Although the conclusions in this thesis increase our understanding of the role of sex steroid hormones in adaptive immunity and vascular pathology, they also raise new questions that warrant further investigation.