Contributions of sex to cerebrovascular function and pathology

• Published in: Brain research Vol. 1710; pp. 43 - 60
• Main Authors: Robison, Lisa S., Gannon, Olivia J., Salinero, Abigail E., Zuloaga, Kristen L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2019
• Subjects: Cerebrovascular disease; Dementia; Sex differences; Sex hormones; Stroke; Vascular; DHEA; eNOS; PR; BBB; TNF-alpha; HIF-1α; ICAM-1; HRT; H2O2; E2; HSD; iNOS; PAI-1; GDX; TBI; AngII; EC; Cerebrovascular disease; 3β-diol; VCID; CAA; CEE; HSP; NFκB; Sex differences; Vascular; IL-1β; ER; AR; MMP; VSM; Sex hormones; TXA2; ET-1; ARE; ZO; ROS; Pgp; ERE; HUVECs; tMCAO; Dementia; NADPH; NO; MCP-1; COX-2; CBF; CNS; LPS; DHT; CBVD; NLS; T; VaD; MCAO; PGE2; 5α–reductase; Stroke; P4; PGI2; VEGF; SOD; ICH; CADASIL; VCAM-1; TJ; GPER; JAM; pMCAO; EDHF; AQP-4
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2018.12.030

[Display omitted] •Sex differences exist in cerebrovascular function and pathology, with many effects mediated by sex hormones.•Throughout most of the lifespan, females are protected from cerebrovascular diseases.•Estrogens are generally protective against cerebrovascular pathology.•Progestins and androgens exert both protective and detrimental effects on the cerebrovasculature.•Effects of sex hormones can vary based on dose, age, and disease state. Sex differences exist in how cerebral blood vessels function under both physiological and pathological conditions, contributing to observed sex differences in risk and outcomes of cerebrovascular diseases (CBVDs), such as vascular contributions to cognitive impairment and dementia (VCID) and stroke. Throughout most of the lifespan, women are protected from CBVDs; however, risk increases following menopause, suggesting sex hormones may play a significant role in this protection. The cerebrovasculature is a target for sex hormones, including estrogens, progestins, and androgens, where they can influence numerous vascular functions and pathologies. While there is a plethora of information on estrogen, the effects of progestins and androgens on the cerebrovasculature are less well-defined. Estrogen decreases cerebral tone and increases cerebral blood flow, while androgens increase tone. Both estrogens and androgens enhance angiogenesis/cerebrovascular remodeling. While both estrogens and androgens attenuate cerebrovascular inflammation, pro-inflammatory effects of androgens under physiological conditions have also been demonstrated. Sex hormones exert additional neuroprotective effects by attenuating oxidative stress and maintaining integrity and function of the blood brain barrier. Most animal studies utilize young, healthy, gonadectomized animals, which do not mimic the clinical conditions of aging individuals likely to get CBVDs. This is also concerning, as sex hormones appear to mediate cerebrovascular function differently based on age and disease state (e.g. metabolic syndrome). Through this review, we hope to inspire others to consider sex as a key biological variable in cerebrovascular research, as greater understanding of sex differences in cerebrovascular function will assist in developing personalized approaches to prevent and treat CBVDs.