Sex differences in neural regulation of hypertension

Abstract

Sex differences in the incidence of hypertension occur as early as adolescence and persist through reproductive senescence both in humans and experimental animals. These sex differences have profound implications for the treatment of not only hypertension but also risk-related cardiovascular diseases. Historically, inadequate tools for identifying specific gonadal hormone receptors have hampered an understanding of the cellular basis of gender differences in hypertension. The emergence of receptor-specific reagents provides the opportunity for a more detailed understanding of the potential cellular sites of action for endogenous and exogenous gonadal hormone receptor ligands. High-resolution electron microscopic imaging employing nanogold and other markers is leading to a reevaluation of gonadal hormone signaling in the brain. One of the most surprising findings is that the neuronal distribution of these receptors frequently occurs at sites classically thought to be the purview of only neurotransmitters and related signaling molecules. We will discuss findings that estrogen receptors are anatomically poised to influence the regulation of blood pressure in response to estrogens in a number of brain regions involved in cardiovascular regulation. We will also present an overview of potential subcellular sites of interaction of estrogen receptors with angiotensin II and related signaling molecules critical for neuronal activation and plasticity in brain cardiovascular regulatory circuits. Since hypertension is known to impair brain health, the role of sex differences in some prevalent hypertension-associated neurological diseases is also discussed. Understanding the mechanisms underlying sex differences in the neural regulation of blood pressure will provide critical new information necessary for understanding the actions of gonadal hormones in the brain, which, in turn, will be critical for the development of new antihypertensive treatments.