Circumventricular Organ Apelin Receptor Knockdown Decreases Blood Pressure and Sympathetic Drive Responses in the Spontaneously Hypertensive Rat.

Philip R Griffiths,Julian F R Paton,Stephen J Lolait,Anne-Marie O’Carroll

doi:10.3389/fphys.2021.711041

Philip R Griffiths, Julian F R Paton + Show 2 more

Open Access

https://doi.org/10.3389/fphys.2021.711041

Copy DOI

Abstract

The central site(s) mediating the cardiovascular actions of the apelin-apelin receptor (APJ) system remains a major question. We hypothesized that the sensory circumventricular organs (CVOs), interfacing between the circulation and deeper brain structures, are sites where circulating apelin acts as a signal in the central nervous system to decrease blood pressure (BP). We show that APJ gene (aplnr) expression was elevated in the CVOs of spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto (WKY) controls, and that there was a greater mean arterial BP (MABP) decrease following microinjection of [Pyr1]apelin-13 to the CVOs of SHRs compared to WKY rats. Lentiviral APJ-specific-shRNA (LV-APJ-shRNA) was used to knockdown aplnr expression, both collectively in three CVOs and discretely in individual CVOs, of rats implanted with radiotelemeters to measure arterial pressure. LV-APJ-shRNA-injection decreased aplnr expression in the CVOs and abolished MABP responses to microinjection of [Pyr1]apelin-13. Chronic knockdown of aplnr in any of the CVOs, collectively or individually, did not affect basal MABP in SHR or WKY rats. Moreover, knockdown of aplnr in any of the CVOs individually did not affect the depressor response to systemic [Pyr1]apelin-13. By contrast, multiple knockdown of aplnr in the three CVOs reduced acute cardiovascular responses to peripheral [Pyr1]apelin-13 administration in SHR but not WKY rats. These results suggest that endogenous APJ activity in the CVOs has no effect on basal BP but that functional APJ in the CVOs is required for an intact cardiovascular response to peripherally administered apelin in the SHR.

Highlights

Dysfunctions in mechanisms that regulate blood pressure (BP) participate in the development of hypertension that is mediated, in part, by activation of the sympathetic nervous system (SNS) (Zubcevic et al, 2011; Fisher and Paton, 2012) or by renal control of peripheral vascular resistance and body fluid volume (Wadei and Textor, 2012)
The present study examines the role of APJ in the sensory circumventricular organs (CVOs) for regulation of arterial pressure in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats
Aplnr is up-regulated in the OVLT, subfornical organ (SFO), and area postrema (AP) in SHRs in comparison to WKY rats

Summary

Introduction

Dysfunctions in mechanisms that regulate blood pressure (BP) participate in the development of hypertension that is mediated, in part, by activation of the sympathetic nervous system (SNS) (Zubcevic et al, 2011; Fisher and Paton, 2012) or by renal control of peripheral vascular resistance and body fluid volume (Wadei and Textor, 2012). The neuropeptide apelin (gene name apln) has wellestablished effects on cardiovascular and BP regulation via central and peripheral targets (O’Carroll et al, 2013) and mediates its effects via activation of the apelin receptor APJ (O’Dowd et al, 1993) (gene name aplnr). Aplnr expression in the PVN is up-regulated in response to acute and repeated stress (O’Carroll et al, 2003), while expression of apln is upregulated in cardiac myocytes by hypoxia (Ronkainen et al, 2007). Insulin elevates both aplnr and apln expression, and apelin production, in adipose tissue (Sörhede Winzell et al, 2005; Dray et al, 2010). The peripheral apelinergic system appears to be down-regulated in hypertensive disease, with changes in the levels of both immunoreactive (ir)-APJ and/or apln/apelin in human (Sonmez et al, 2010; Chandra et al, 2011; Zhu et al, 2013) and some rodent hypertension models (Zhang et al, 2006)

Methods

Results

Conclusion