Cytokines Driving Sympathetic Nervous System Activation in the Subfornical Organ: Implications for Heart Failure and Hypertension

subfornical organ
Subfornical Organ – Heart Failure – Hypertension

A recent study published in Hypertension demonstrates that cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α acting at the level of the subfornical organ induce the expression of inflammatory and excitatory mediators that subsequently drive sympathetic nervous system activation.

The subfornical organ (SFO), a highly vascularized structure is a circumventricular organ that lacks a blood–brain barrier. Previous research indicates this brain structure is a crucial ‘sensor’ for peripheral inflammation, mediating the central effects of certain pro-inflammatory cytokines, and thus, contributing to an increase in autonomic and neuro-hormonal output.

The SFO is rich in angiotensin-converting enzyme (ACE) and in angiotensin II (ANG II) type-1 receptors (AT1R), key components of the brain renin–angiotensin system (RAS) that activates subfornical organ neurons and drives sympathetic nerve activity in pathophysiological states like hypertension and HF. PICs contribute to upregulation of brain RAS activity in the hypothalamic paraventricular nucleus (PVN), another brain region that has been implicated in the sympathetic excitation and cardiovascular dysfunction, in hypertension and HF.

Cyclooxygenase (COX), the key enzyme regulating the production of prostaglandin E2 (PGE2), is also abundantly expressed in the highly vascularized SFO. PGE2 increases the firing rate of subfornical organ neurons by disinhibiting inhibitory γ-aminobutyric acid inputs. ANG II infusion induced hypertension is reportedly dependent on the activity of constitutively expressed COX-1 in the subfornical organ, and PIC-dependent induction of COX-2 in perivascular macrophages has been implicated in the pathophysiology of HF. Thus, inflammatory mechanisms that increase brain RAS activity or PGE2 production in SFO might be expected to increase sympathetic nerve activity.

In the Hypertension study Shun-Guang Wei and colleagues from the University of Iowa Carver College of Medicine, Iowa City, IA examined potential mechanisms in the subfornical organ, and downstream in the PVN, that might mediate cardiovascular and autonomic responses to circulating PICs.

The investigators report that (1) localized microinjections of TNF-α and IL-1β into the SFO increase BP, HR, and RSNA, closely mimicking the effects of systemically administered TNF-α and IL-1β; (2) pretreating the SFO with microinjections of agents that counter RAS and COX-2 activity attenuates the cardiovascular and sympathetic responses to SFO microinjections of PICs; (3) TNF-α and IL-1β receptor immunoreactivity is colocalized with AT1R-like, ACE, COX-2, and EP3 receptor immunoreactivity on subfornical organ neurons; and (4) subfornical organ microinjections of TNF-α and IL-1β upregulate mRNA for key components of the RAS (ACE and AT1R) and mediators of central inflammation (TNF-α and IL-1β, their receptors and COX-2) in both SFO and PVN.

These findings suggest that the SFO-mediated acute sympathoexcitatory response to PICs depends on the ambient level of RAS and COX-2 activity and that PICs act within the subfornical organ to increase RAS and COX-2 activity.

The authors provide evidence that IL-1β and TNF-α up-regulate mediators and mechanisms that increase the brain renin–angiotensin system (RAS) activity or prostaglandin E2 production in the SFO of male Sprague–Dawley rats.

This study provides new insights into the central mechanisms driving neurohumoral excitation in cardiovascular disorders like HF and hypertension.

The SFO is directly exposed to blood-borne signals and peripheral cytokines, and it projects straight to the cardiovascular autonomic nuclei.

The authors suggest that through the above mentioned effects and mechanisms, peripheral pro-inflammatory cytokines are able to drive a chronic and sustained hyperactivity of the sympathetic nervous system observed in pathologic states such as heart failure or some forms of hypertension.

In addition, according to the authors, these mechanisms and pathogenic loops can be amplified by other excitatory mediators, like angiotensin II and aldosterone that circulate in chronic states like heart failure and hypertension.

Source: Hypertension, 2015, 65:1126-33. doi: 10.1161/HYPERTENSIONAHA.114.05112. Epub 2015 Mar 16.
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