Angiotensin II-Driven Mechanisms of Neuroinflammation in the Maintenance of Hypertension

Abstract

Hypertension, one of the most prevalent cardiovascular risk factors, exhibits numerous pathophysiologies and is typically attributed to dysregulation of the cardiovascular, renal, and/or central nervous systems (CNS). Whereas the contributions of adaptive immune system activation to high blood pressure are well documented, the molecular mechanisms that activate the innate immune system and lead to priming/activation of the adaptive immune response are not fully understood. The innate immune system identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream proinflammatory signaling cascades and shapes the adaptive immune response. Accumulating evidence from the past decade indicates that a hyperactive innate immune system response, particularly via Toll-like receptor (TLR) stimulation, fosters chronic inflammation in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression. A putative TLR4 ligand, angiotensin II (AngII), is the primary signaling peptide of the renin-angiotensin system (RAS). Within the CNS, AngII stimulates the production of pro-inflammatory cytokines, increases sympathetic nervous system activity, and is implicated as a driving force behind blood-brain barrier (BBB) disruption in neurogenic hypertension. Our prior work shows that AngII type 1 receptor (AT1R) blockade restores BBB integrity in CNS cardioregulatory nuclei (i.e., the hypothalamic paraventricular nucleus [PVN], rostral ventrolateral medulla [RVLM], and nucleus tractus solitarius [NTS]), and that exogenous AngII stimulates TLR4 via AT1R in hypothalamic microglia ex vivo, resulting in microglial activation. The aim of the studies herein was to determine the contribution of AT1R-TLR4 signaling interactions to BBB disruption, neuroinflammation, and autonomic dysfunction in neurogenic hypertension. Spontaneously hypertensive rats (SHRs) were treated with Losartan (AT1R inhibitor) or TAK-242 (TLR4 inhibitor) and age-matched to control Wistar Kyoto rats (WKYs). AT1R and TLR4 inhibitions normalized increased TLR4 protein density in the PVN, RVLM, and NTS of SHRs versus WKYs. Losartan and TAK-242 downregulated elevated interleukin-6 and tumor necrosis factor-α densities and abolished enhanced microglial activation in SHR central cardioregulatory nuclei. PVN, RVLM, and NTS BBB permeability analyses revealed complete restoration after TAK-242 treatment, whereas dye leakage, indicative of BBB disruption, was elevated in SHR. Elevated indirect mean arterial pressure was normalized in Losartan-treated SHRs and attenuated with TLR4 inhibition. During conscious baroreflex sensitivity assessment, TLR4 blockade rescued SHR responsiveness to vasoactive drugs. Ganglionic blockade induced a greater pressor response in SHRs compared to WKYs that was abolished by TLR4 inhibition. Overall, our data suggest a feed-forward pro-hypertensive cycle involving BBB disruption, neuroinflammation, and autonomic dysfunction driven by AngII-induced AT1R-TLR4 signaling interactions.