Abstract
Dysfunction of the apelinergic system, comprised of the neuropeptide apelin mediating its effects via the G protein-coupled apelin receptor (APJ), may underlie the onset of cardiovascular disease such as hypertension. Apelin expression is increased in the rostral ventrolateral medulla (RVLM) in spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) normotensive rats, however, evidence that the apelinergic system chronically influences mean arterial blood pressure (MABP) under pathophysiological conditions remains to be established. In this study we investigated, in conscious unrestrained rats, whether APJ contributes to MABP and sympathetic vasomotor tone in the progression of two models of hypertension – SHR and L-NAME-treated rats – and whether APJ contributes to the development of hypertension in pre-hypertensive SHR. In SHR we showed that APJ gene (aplnr) expression was elevated in the RVLM, and there was a greater MABP increase following microinjection of [Pyr1]apelin-13 to the RVLM of SHR compared to WKY rats. Bilateral microinjection of a lentiviral APJ-specific-shRNA construct into the RVLM of WKY, SHR, and L-NAME-treated rats, chronically implanted with radiotelemeters to measure MABP, decreased aplnr expression in the RVLM and abolished acute [Pyr1]apelin-13-induced increases in MABP. However, chronic knockdown of aplnr in the RVLM did not affect MABP in either SHR or L-NAME-treated rats. Moreover, knockdown of aplnr in the RVLM of prehypertensive SHR did not protect against the development of hypertension. These results show that endogenous apelin, acting via APJ, is not involved in the genesis or maintenance of hypertension in either animal model used in this study.
Highlights
The brainstem plays a vital role in blood pressure (BP) regulation through an intricate signaling network that modulates sympathetic nerve activity (SNA) and secretes hormones into the circulation to maintain a homeostatic BP (Fisher and Paton, 2012)
As recent reports imply that central apelin-13 may contribute to BP regulation and play a causative role in neurogenic hypertension, we hypothesized that APJ signaling in the rostral ventrolateral medulla (RVLM) may contribute to the development of hypertension through regulation of SNA and that targeting this central APJ pathway may be an important new strategy in modulating sympathetic outflow to reverse or prevent hypertensive pathology
Associated with cardiovascular function, and recent work has shown that bilateral microinjection of [Pyr1]apelin-13 into this region increases sympathetic vasomotor tone and BP (Zhang et al, 2009)
Summary
The brainstem plays a vital role in blood pressure (BP) regulation through an intricate signaling network that modulates sympathetic nerve activity (SNA) and secretes hormones into the circulation to maintain a homeostatic BP (Fisher and Paton, 2012). Increasing evidence supports a role for the neuropeptide apelin as a key regulator of central and peripheral responses to Chronic APJ Knockdown in RVLM homeostatic perturbations including the control of fluid homeostasis (O’Carroll and Lolait, 2003), food intake (Taheri et al, 2002) and angiogenesis (Liu et al, 2015). The apelinergic system is richly expressed in central neural circuits that are involved in the modulation of BP, including the medial parvocellular paraventricular nucleus (PVN) (Lee et al, 2000; O’Carroll et al, 2000), the cerebroventricular system, and lower brainstem structures such as the rostral ventrolateral medulla (RVLM) (Lee et al, 2000; Brailoiu et al, 2002; Reaux et al, 2002). Apln and aplnr transcripts are expressed in discrete brain regions that position them to be potential chronic modulators of cardiovascular tone
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