1. Academic Validation
  2. TLR4 and AT1R mediate blood-brain barrier disruption, neuroinflammation, and autonomic dysfunction in spontaneously hypertensive rats

TLR4 and AT1R mediate blood-brain barrier disruption, neuroinflammation, and autonomic dysfunction in spontaneously hypertensive rats

  • Pharmacol Res. 2021 Dec;174:105877. doi: 10.1016/j.phrs.2021.105877.
Francesca E Mowry 1 Sarah C Peaden 2 Javier E Stern 3 Vinicia C Biancardi 4
Affiliations

Affiliations

  • 1 Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA; Center for Neurosciences Initiative, Auburn University, Auburn, AL, USA.
  • 2 Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
  • 3 Center for Neuroinflammation, Georgia State University, Atlanta, GA, USA.
  • 4 Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA; Center for Neurosciences Initiative, Auburn University, Auburn, AL, USA. Electronic address: vbiancardi@auburn.edu.
Abstract

Angiotensin II (AngII) is implicated in neuroinflammation, blood-brain barrier (BBB) disruption, and autonomic dysfunction in hypertension. We have previously shown that exogenous AngII stimulates Toll-like Receptor 4 (TLR4) via AngII type 1 receptor (AT1R), inducing activation of hypothalamic microglia ex vivo, and that AngII-AT1R signaling is necessary for the loss of BBB integrity in spontaneously hypertensive rats (SHRs). Herein, we hypothesized that microglial TLR4 and AT1R signaling interactions represent a crucial mechanistic link between AngII-mediated neuroinflammation and BBB disruption, thereby contributing to sympathoexcitation in SHRs. Male SHRs were treated with TAK-242 (TLR4 inhibitor; 2 weeks), Losartan (AT1R inhibitor; 4 weeks), or vehicle, and age-matched to control Wistar Kyoto rats (WKYs). TLR4 and AT1R inhibitions normalized increased TLR4, interleukin-6, and tumor necrosis factor-α protein densities in SHR cardioregulatory nuclei (hypothalamic paraventricular nucleus [PVN], rostral ventrolateral medulla [RVLM], and nucleus tractus solitarius [NTS]), and abolished enhanced microglial activation. PVN, RVLM, and NTS BBB permeability analyses revealed complete restoration after TAK-242 treatment, whereas SHRs presented with elevated dye leakage. Mean arterial pressure was normalized in Losartan-treated SHRs, and attenuated with TLR4 inhibition. In conscious assessments, TLR4 blockade rescued SHR baroreflex sensitivity to vasoactive drugs, and reduced the SHR pressor response to ganglionic blockade to normal levels. These data suggest that TLR4 activation plays a substantial role in mediating a feed-forward pro-hypertensive cycle involving BBB disruption, neuroinflammation, and autonomic dysfunction, and that TLR4-specific therapeutic interventions may represent viable alternatives in the treatment of hypertension.

Keywords

Angiotensin II; Blood-brain barrier; Hypertension; Microglia; Neuroinflammation; TAK-242 (PubChem CID: 11703255); Toll-like receptor 4; hexamethonium bromide (PubChem CID: 24278459); losartan (PubChem CID: 11751549); phenylephrine hydrochloride (PubChem CID: 5284443); sodium nitroprusside dehydrate (PubChem CID: 11953895).

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