TNF-α-induced sympathetic excitation requires EGFR and ERK1/2 signaling in cardiovascular regulatory regions of the forebrain

Am J Physiol Heart Circ Physiol. 2021 Feb 1;320(2):H772-H786. doi: 10.1152/ajpheart.00606.2020. Epub 2020 Dec 18.

Abstract

Peripherally or centrally administered TNF-α elicits a prolonged sympathetically mediated pressor response, but the underlying molecular mechanisms are unknown. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cardiovascular regions of the brain has recently been recognized as a key mediator of sympathetic excitation, and ERK1/2 signaling is induced by activation of epidermal growth factor receptor (EGFR) tyrosine kinase activity. The present study examined the role of EGFR and ERK1/2 signaling in the sympathetic response to TNF-α. In urethane-anesthetized rats, intracarotid artery injection of TNF-α increased phosphorylation of EGFR and ERK1/2 in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN); upregulated the gene expression of excitatory mediators in SFO and PVN; and increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA). A continuous intracerebroventricular infusion of the selective EGFR tyrosine kinase inhibitor AG1478 or the ERK1/2 inhibitor PD98059 significantly attenuated these responses. Bilateral PVN microinjections of TNF-α also increased phosphorylated ERK1/2 and the gene expression of excitatory mediators in PVN, along with increases in BP, HR, and RSNA, and these responses were substantially reduced by prior bilateral PVN microinjections of AG1478. These results identify activation of EGFR in cardiovascular regulatory regions of the forebrain as an important molecular mediator of TNF-α-driven sympatho-excitatory responses and suggest that EGFR activation of the ERK1/2 signaling pathway plays an essential role. These mechanisms likely contribute to sympathetic excitation in pathophysiological states like heart failure and hypertension, in which circulating and brain TNF-α levels are increased.NEW & NOTEWORTHY Proinflammatory cytokines contribute to the augmented sympathetic nerve activity in hypertension and heart failure, but the central mechanisms involved are largely unknown. The present study reveals that TNF-α transactivates EGFR in the subfornical organ and the hypothalamic paraventricular nucleus to initiate ERK1/2 signaling, upregulate the gene expression of excitatory mediators, and increase sympathetic nerve activity. These findings identify EGFR as a gateway to sympathetic excitation and a potential target for intervention in cardiovascular disease states.

Keywords: brain; hypothalamic paraventricular nucleus; proinflammatory cytokines; renin-angiotensin system; subfornical organ; sympathetic nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Cardiovascular System / innervation*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Heart Rate / drug effects
  • Hemodynamics / drug effects*
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphorylation
  • Prosencephalon / drug effects*
  • Prosencephalon / enzymology
  • Protein Kinase Inhibitors / pharmacology
  • Quinazolines / pharmacology
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sympathetic Nervous System / drug effects*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tyrphostins / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • Tumor Necrosis Factor-alpha
  • Tyrphostins
  • RTKI cpd
  • Egfr protein, rat
  • ErbB Receptors
  • Mapk1 protein, rat
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3