Role of olfactory receptor78 in carotid body-dependent sympathetic activation and hypertension in murine models of chronic intermittent hypoxia

Abstract

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread breathing disorder. CIH treated rodents exhibit activation of the sympathetic nervous system and hypertension. Heightened carotid body (CB) activity has been implicated in CIH-induced hypertension. CB expresses high abundance of olfactory receptor (Olfr) 78, a G-protein coupled receptor. Olfr 78 null mice exhibit impaired CB sensory nerve response to acute hypoxia. Present study examined whether Olfr78 participates in CB-dependent activation of the sympathetic nervous system and hypertension in CIH treated mice and in hemeoxygenase (HO)-2 null mice experiencing CIH as a consequence of naturally occurring OSA. CIH treated wild type (WT) mice showed hypertension, bio-markers of sympathetic nerve activation, and enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), and these responses were absent in CIH treated Olfr78 null mice. HO-2 null mice showed higher apnea index (AI) (58±1.2 apneas/hour) than WT mice (AI= 8±0.8 apneas/hour), and exhibited elevated blood pressure (BP), plasma NE levels and heightened CB sensory nerve response to hypoxia and sLTF. The magnitude of hypertension correlated with AI in HO-2 null mice. In contrast, HO-2/Olfr78 double null mice showed absence of elevated BP, plasma NE levels, augmented CB response to hypoxia and sLTF. These results demonstrate that Olfr78 participates in sympathetic nerve activation and hypertension, and heightened CB activity in two murine models of CIH.

Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release

“…While it is not possible to perfectly mimic OSA by exposing mice or cells to IH exposure, our published data, measuring blood gases, and other reference points support the use of in vitro and in vivo models of IH that we employed in our studies ( Peng and Prabhakar, 2003 , 2004 ). We did not measure blood pressure in the current study as an endpoint to determine whether mice were exposed equally to IH; however, we have recently reported blood pressure responses to IH in non-sedated mice using tail-cuff method as well as a telemetry approach ( Peng et al, 2006 , 2021 ). Both approaches showed significant elevation of both systolic and diastolic blood pressure in C57BL/6 mice treated with IH for 10 days.…”

“…Mechanistically, OSA is characterized by collapse of the upper airway causing recurrent pauses in breathing during sleep leading to intermittent hypoxemia (IH), arousals, changes in intrathoracic pressure, and sleep fragmentation ( Somers et al, 1995 ; Gabryelska et al, 2018 ). Furthermore, patients with OSA exhibit increased sympathetic nerve activity ( Dempsey et al, 2010 ; Prabhakar, 2016 ) as well as elevated circulating and urinary catecholamines (both norepinephrine and epinephrine), which are attributed to heightened sympathetic nerve activity ( Fletcher et al, 1987 ; Carlson et al, 1993 ; Marrone et al, 1993 ; Somers et al, 1995 ; Peng et al, 2021 ). IH is a hallmark manifestation of OSA and thought to be a major factor contributing to the pathogenesis of OSA-related cardiovascular morbidity.…”

Olfactory receptor 78 is expressed in hypothalamic vasopressin/oxytocin neurons, parenchymal microglia and choroidal macrophages in mice

“…Therefore, we concluded that at least some oxytocin neurons expressed Olfr78. Previous reports have demonstrated that Olfr78 is expressed in cells with chemosensory properties[ 3 , 5 , 6 , 9 ]. Olfr78 responds to various small fatty acids, while the endogenous ligand for Olfr78 remains undetermined [ 4 , 10 , 12 ].…”

“…Their extraolfactory expression has been intensively investigated and is increasingly reported. One olfactory receptor superfamily member, olfactory receptor 78 (Olfr78), is widely expressed, for example, in the brain [ 1 ] kidney [ 2 ], arterioles [ 3 , 4 ], carotid body [ 5 ], macrophages [ 6 ], colon [ 7 ], and prostate [ 3 ].…”

“…Olfr78 is related to hypoxia-associated responses in the kidney and the carotid body [ 2 , 5 ] and to bacterial metabolite sensing and hormone secretion in the colon [ 7 ]. In the prostate, Olfr78 is related to tumorigenesis and is also called prostate-specific GPCR (PSGR) [ 8 ].…”