Androgens' effects on cerebrovascular function in health and disease

Abstract

Androgens affect the cerebral vasculature and may contribute to sex differences in cerebrovascular diseases. Men are at a greater risk for stroke and vascular contributions to cognitive impairment and dementia (VCID) compared to women throughout much of the lifespan. The cerebral vasculature is a target for direct androgen actions, as it expresses several sex steroid receptors and metabolizing enzymes. Androgens' actions on the cerebral vasculature are complex, as they have been shown to have both protective and detrimental effects, depending on factors such as age, dose, and disease state. When administered chronically, androgens are shown to be pro-angiogenic, promote vasoconstriction, and influence blood-brain barrier permeability. In addition to these direct effects of androgens on the cerebral vasculature, androgens also influence other vascular risk factors that may contribute to sex differences in cerebrovascular diseases. In men, low androgen levels have been linked to metabolic and cardiovascular diseases including hypertension, diabetes, hyperlipidemia, and obesity, which greatly increase the risk of stroke and VCID. Thus, a better understanding of androgens' interactions with the cerebral vasculature under physiological and pathological conditions is of key importance.

Keywords: Androgens; Blood-brain barrier; Cerebral vasculature; Cerebrovascular disease; Dihydrotestosterone; Endothelial; Hormone therapy; Stroke; Testosterone; Vascular contributions to cognitive impairment and dementia.

Fig. 1

Androgen metabolism and signaling in the cerebral vasculature. Signaling pathways are indicated using green arrows. Metabolic pathways are indicated using blue arrows, and metabolizing enzymes are in purple. Confirmed expression in cells of the cerebral vasculature is indicated by cartoon cell types (see key). AR, androgen receptor; ER, estrogen receptor; HSD, Hydroxysteroid dehydrogenase; ZIP9, Zrt- and Irt-like protein 9; GPRC6a, G-protein-coupled receptor C6A; GPER1, G-protein-coupled estrogen receptor

Fig. 2

Effects of androgens on cerebrovascular function. Green arrows represent promotion of the function, while red lines with rectangles at ends represent inhibition of the function. Mechanisms by which these effects have been shown to occur in the cerebral vasculature are listed along the lines. COX-2, cyclooxygenase 2; CLDN5, claudin-5; EPC, endothelial progenitor cell; HIF-1α, hypoxia- inducible factor 1-alpha; iNOS, inducible nitric oxide synthase; TXA2, thromboxane A2; SRT1, Sirtuin 1; VCID, vascular contributions to cognitive impairment and dementia; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor 2; ZO1, tight junction protein ZO-1

Fig. 3

Interaction between androgens and cerebrovascular disease risk factors. a Schematic representation of risk factors influencing or correlating with androgen levels in males and females. b Schematic representation of how androgen levels affect/correlate with risk factors for cerebrovascular diseases. Relations are shown in pink in females, and those in males are shown in blue. T/E2, testosterone to estrogen ratio increases after menopause in females

Fig. 4

Schematic representation of testosterone levels during adulthood. Plasma testosterone levels (relative to those found in young men) are plotted during adulthood in men (blue) and women (pink)