Oxytocin Receptor Signaling in Vascular Function and Stroke

Way beyond my ability to understand how this might help in stroke recovery.

Oxytocin Receptor Signaling in Vascular Function and Stroke

Erin C. McKay^1,2* and Scott E. Counts^1,2,3,4,5

• ¹Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, United States
• ²Neuroscience Program, Michigan State University, East Lansing, MI, United States
• ³Department of Family Medicine, Michigan State University, Grand Rapids, MI, United States
• ⁴Hauenstein Neurosciences Center, Mercy Health Saint Mary’s Hospital, Grand Rapids, MI, United States
• ⁵Michigan Alzheimer’s Disease Research Center, Ann Arbor, MI, United States

The oxytocin receptor (OXTR) is a G protein-coupled receptor with a diverse repertoire of intracellular signaling pathways, which are activated in response to binding oxytocin (OXT) and a similar nonapeptide, vasopressin. This review summarizes the cell and molecular biology of the OXTR and its downstream signaling cascades, particularly focusing on the vasoactive functions of OXTR signaling in humans and animal models, as well as the clinical applications of OXTR targeting cerebrovascular accidents.

Introduction

Since its original cloning and characterization by Kimura et al. (1992), to more recent predictions of its three dimensional structure (Busnelli et al., 2016), the human oxytocin receptor (OXTR) has garnered special attention for its role as a potential therapeutic target in a wide array of physiological and behavioral disorders. Several recent reviews have comprehensively covered the impact of OXTR signaling upon peripheral and central control of behavior and physiological functions including osmoregulatory, stress modulation, and memory (Jurek and Neumann, 2018; Grinevich and Neumann, 2020). By contrast, this review will survey the role of OXTR-mediated cellular and molecular pathways regulating vascular function, with a special focus on mechanisms of cerebrovascular disease and the receptor’s putative disease-modifying role in the post-stroke environment, which may be amenable to therapeutic targeting.

The Oxytocin Receptor

The OXTR is a widely expressed G_αq protein-coupled receptor (GPCR) that binds its endogenous nonapeptide ligand, oxytocin (OXT), with an affinity of about 1–10 nM (Chini et al., 2017), as well as a structurally similar nonapeptide, vasopressin, with an affinity of about 100 nM–1 μM (Postina et al., 1996). The OXT peptide and its full nine amino acid sequence was first detailed in 1953 by Du Vigneaud and colleagues through varied partial hydrolysis experiments combined with paper chromatography (du Vigneaud et al., 1953). However, its existence was recognized as early as 1928 when researchers began testing the effects of OXT from pituitary extracts on peripheral reactions such as uterine contractions and blood pressure (Bourne and Burn, 1928; Griling and Eddy, 1928; Gruber, 1928; Kamm et al., 1928). OXT has since been found to exert both central and peripheral effects via OXTR-mediated phospholipase C (PLC) activation and downstream Ca²⁺ signal transduction (Zingg and Laporte, 2003). OXT is synthesized in the hypothalamic magnocellular and parvocellular neurons, reaching the peripheral circulation through the posterior pituitary (Argiolas and Gessa, 1991), while central actions appear to occur through both axonal and possibly volume transmission through dendrites (Meyer-Lindenberg et al., 2011). This volume transmission and its relative contribution to OXTR activation is an ongoing subject of debate, as more OXT neuronal projections to forebrain OXTR-expressing regions have become apparent in recent years (Knobloch et al., 2012; Grinevich et al., 2016). The very first hint of a bioactive OXTR was indirectly demonstrated by Sir Henry Dale and focused on the induction of uterine contractions by posterior pituitary gland components (Viero et al., 2010). Since that time OXTRs have not only been identified in the uterus (Fuchs et al., 1984), but also the mammary glands (Soloff et al., 1977), heart (Gutkowska et al., 1997), blood vessels (Thibonnier et al., 1999b), and brain (Muhlethaler et al., 1983). While the presence and activity of the receptor in each of these regions underscores the importance of OXTR signaling in peripheral and central physiology, this review will focus primarily on those found in the brain. Regardless, the widespread expression of this receptor and its ligands underscores the continued relevance and necessity of research into its functional repertoire (Grinevich et al., 2016), even after the 100 years that have passed since Dale engaged the receptor without knowing what it was (Viero et al., 2010). Before turning to physiological and disease modifying possibilities for the receptor, its biology as revealed by basic research will be summarized. This section provides a synthesis of the current understanding of the OXTR gene and protein at the cellular level that will be necessary to fully grasp the potential of its therapeutic use.

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