Epidermal Growth Factor Receptor in the Hypothalamic Paraventricular Nucleus Contributes to Tumor Necrosis Factor‐α‐Induced Sympathetic Excitation in Rat

Abstract

Epidermal growth factor receptor (EGFR) is reported to mediate various functions of angiotensin II and aldosterone in peripheral cardiovascular tissues and has been shown to activate p44/42 mitogen‐activated protein kinase, also known as extracellular signal‐regulated kinases 1 and 2 (ERK1/2), an excitatory mediator for sympathetic drive when phosphorylated. Our previous study indicated that EGFR in the brain can mediate the hemodynamic and sympathic responses in response to systemically administered aldosterone. The present work sought to determine whether EGFR tyrosine kinase activation in the brain, particularly in the hypothalamic paraventricular nucleus (PVN), contributes to sympathetic excitation induced by the pro‐inflammatory cytokine tumor necrosis factor (TNF)‐α. In urethan‐anesthetized rats, mean blood pressure (MBP, mmHg), heart rate (HR, beats/min) and renal sympathetic nerve activity (RSNA, % change from baseline), were recorded in two experimental settings: 1). intracarotid artery (ICA) bolus injection of TNF‐α (200 ng) 10 min after initiating a 4‐hour intracerebroventricular (ICV) infusion of the EGFR inhibitor AG1478 (200 ng/hr) or vehicle; 2). bilateral PVN microinjection of TNF‐α (10 ng/side) 10 min after bilateral PVN microinjection of the EGFR inhibitor AG1478 (50 ng/side). ICA injection of TNF‐α induced a substantial and long‐lasting increase in MBP (19.3 ± 2.7), HR (79.8 ± 9.7) and RSNA (89.3 ± 9.1), with the peak responses at 1.5 to 3 hours in ICV vehicle treated rats (n=6). These pressor responses to ICA TNF‐α were significantly reduced (MBP: 8.9 ± 2.0; HR: 41.5 ± 7.6; RSNA: 47.1 ± 9.5) in the rats treated with ICV AG1478 (n=6). ICA TNF‐α also induced phosphorylation (activation) of ERK1/2 in the PVN, an effect that was attenuated in rats pretreated with ICV AG1478. Bilateral PVN microinjection of TNF‐α (n=6), like ICA TNF‐α, elicited excitatory responses in MBP (14.1 ± 1.8), HR (60.3 ± 4.2) and RSNA (66.1 ± 5.0) in rats pretreated with bilateral PVN microinjection of vehicle. The peak responses occurred 1.5–2.5 hours after microinjection of TNF‐α. Rats pretreated with bilateral PVN microinjection of AG1478 (n=6) had significantly attenuated excitatory responses to bilateral PVN microinjection of TNF‐α (MBP: 7.6 ± 1.2; HR: 36.7 ± 3.0; RSNA: 40.2 ± 3.5). These data indicate that activation of brain EGFR is required for the full expression of the cardiovascular and sympathic effects of blood‐borne or centrally administered TNF‐α. EGFR tyrosine kinase activated by TNF‐α in the PVN plays an essential role in this process, and EGFR activation of ERK1/2 signaling may contribute. These findings in normal rats suggest that EGFR may be an important molecular mechanism contributing to inflammation‐driven sympathetic activation in heart failure and hypertension, and a potential target for therapeutic interventions.Support or Funding InformationSupported by NIH RO1 HL073986, HL136149 and the Department of Veterans Affairs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.