Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

Abstract

GPR37L1 is a family A orphan G protein-coupled receptor (GPCR) with a putative role in blood pressure regulation and cardioprotection. In mice, genetic ablation of Gpr37l1 causes sex-dependent effects; female mice lacking Gpr37l1 (GPR37L1−/−) have a modest but significant elevation in blood pressure, while male GPR37L1−/− mice are more susceptible to cardiovascular dysfunction following angiotensin II-induced hypertension. Given that this receptor is highly expressed in the brain, we hypothesize that the cardiovascular phenotype of GPR37L1−/− mice is due to changes in autonomic regulation of blood pressure and heart rate. To investigate this, radiotelemetry was employed to characterize baseline cardiovascular variables in GPR37L1−/− mice of both sexes compared to wildtype controls, followed by power spectral analysis to quantify short-term fluctuations in blood pressure and heart rate attributable to alterations in autonomic homeostatic mechanisms. Additionally, pharmacological ganglionic blockade was performed to determine vasomotor tone, and environmental stress tests were used to assess whether cardiovascular reactivity was altered in GPR37L1−/− mice. We observed that mean arterial pressure was significantly lower in female GPR37L1−/− mice compared to wildtype counterparts, but was unchanged in male GPR37L1−/− mice. GPR37L1−/− genotype had a statistically significant positive chronotropic effect on heart rate across both sexes when analyzed by two-way ANOVA. Power spectral analysis of these data revealed a reduction in power in the heart rate spectrum between 0.5 and 3 Hz in female GPR37L1−/− mice during the diurnal active period, which indicates that GPR37L1−/− mice may have impaired cardiac vagal drive. GPR37L1−/− mice of both sexes also exhibited attenuated depressor responses to ganglionic blockade with pentolinium, indicating that GPR37L1 is involved in maintaining sympathetic vasomotor tone. Interestingly, when these mice were subjected to aversive and appetitive behavioral stressors, the female GPR37L1−/− mice exhibited an attenuation of cardiovascular reactivity to aversive, but not appetitive, environmental stimuli. Together, these results suggest that loss of GPR37L1 affects autonomic maintenance of blood pressure, giving rise to sex-specific cardiovascular changes in GPR37L1−/− mice.

Metabolic Profiling of Mice with Deletion of the Orphan G Protein-Coupled Receptor, GPR37L1

“…An interesting observation was that Gpr37l1 −/− exhibited significantly lower ambulatory activity than wildtype controls during their active period. This was not seen in the younger chow-fed mice in this study, though a previous study in this same mouse line that measured locomotor activity by radiotelemetry reported significantly lower activity in male Gpr37l1 −/− mice at 14–15 weeks old [ 10 ]. These differences in activity between Gpr37l1 −/− mice and their wildtype controls were not associated with significant genotype effects on energy expenditure or body weight in the aged mice.…”

“…The present study was designed to investigate the metabolic effects of the deletion of Gpr37l1 in mice, by thoroughly characterising the metabolic profile of Gpr37l1 −/− mice compared with wildtype ( Gpr37l1 +/+ ; C57BL/6J background) littermate controls. We have previously characterised this Gpr37l1 knockout mouse line and used it in studies investigating the cardiovascular effects of GPR37L1 [ 9 , 10 ], and this study investigates heretofore unexplored metabolic roles for this receptor. We chose to approach this question from two angles, using a high-fat diet (HFD) feeding protocol to investigate possible differences in the onset of obesity in these mice ( Figure 1 a,b), alongside a longitudinal cohort to investigate any changes in body composition over one year ( Figure 1 c).…”

“…GPR37L1 is an understudied orphan GPCR [ 31 , 32 ] and its physiological role is not well understood, though it has been previously proposed to have various effects on cardiovascular and nervous systems [ 7 , 8 , 9 , 10 , 33 , 34 ]. This study represents the first investigation of the potential metabolic effects of GPR37L1.…”

“…Here, we use male Gpr37l1 knockout mice on a C57BL/6J background (hereafter referred to as “ Gpr37l1 −/− ”). These have previously been characterised and validated as Gpr37l1 −/− mice by Western blot and RT-qPCR [ 9 ], and have been used previously by our laboratory to investigate the cardiovascular effects of GPR37L1 [ 9 , 10 ]. We have also confirmed the genotype of all experimental mice ( Supplementary Figure S1 ) to verify deletion of Gpr37l1 .…”

“…The known physiological effects of GPR37L1 include cerebellar development [ 7 ], neuroprotection [ 8 ] and involvement in cardiovascular homeostasis [ 9 , 10 ], but as yet a metabolic role for this receptor has not been described. There is some evidence to suggest that GPR37L1 may have an effect on body weight homeostasis: genetic deletion of the receptor most closely related to GPR37L1, GPR37, induced lower body weight in mice [ 11 ], which may be relevant given the sequence similarity and pattern of expression in the brain of these two related receptors.…”