Brain-Splenic Nerve Axis Hypertension

Brain-Splenic Nerve Axis: Role in Hypertension

Brain-Splenic Nerve Axis – Hypertension

A recent Nature Communications study indicates that the brain-splenic nerve axis is involved in hypertension. Moreover, it is linked to T cell activation and an egression of T-cells from the spleen, a process dependent on the vagus-splenic nerve connection.

Hypertension is a major risk factor for coronary heart diseases and stroke. Despite various therapeutic approaches 10-15% of the general hypertensive population is drug-resistant. On the other hand, severe hypotension is a life-threating condition commonly found during conditions such as sepsis and septic shock.

For many years hypertension was considered purely a dysfunction of the autonomic or sympathetic nervous systems. In recent years, however, the brain-immune system connection is emerging as a new concept and mechanism contributing to hypertension.

In the last decade, immunity emerged as a crucial player in hypertension: immune cells infiltrate the vessel walls and kidneys of hypertensive animals, and mice without lymphocytes are protected from angiotensinII (AngII)-induced hypertension.

Lymphoid organs, including the spleen, are densely innervated primarily by the sympathetic nervous system (SNS). The SNS regulates all major immune functions including regulatory T cells’ activity and leukocyte traffic and distribution.

Recently, it has become increasingly clear that T cells and inflammation are involved in the genesis of hypertension. Thus, T cells and monocyte/macrophages infiltrate the kidney and perivascular regions of both large arteries and arterioles and these adaptive and innate and immune cells contribute to end-organ damage and dysfunction in hypertension. In addition, blood pressure is also affected by CD4+ T lymphocytes that express choline acetyltransferase (ChAT).

Preliminary studies indicated that splanchnic innervation would impact hypertension. However, two main questions remain unanswered: (i) which splanchnic nervous compartment is responsible for these effects on immunity and blood pressure regulation and (ii) how is the brain-to-splanchnic compartment connection established at the onset of hypertension.

In the Nature Communications study, Daniela Carnevale and colleagues from the Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy report that an experimental angiotensin II-induced hypertension is associated with a splenic sympathetic nerve discharge. Carnevale et al. demonstrate that the stimulation of the splenic sympathetic nerves are mediated by a vagal-coeliac-splenic connection.

In this study coeliac vagotomized animals were protected from the hypertensive effects of the angiotensin II administration. Also, animals lacking α7 nicotinic acetylcholine receptor (α7nAChR) did not present with an increased splenic nerve activity following angiotensin II.

Of note, vagus nerve efferents are known to terminate in the coeliac plexus ganglia where the sympathetic/catecholaminergic fibres of the splenic nerve originate.

Thus, these experiments suggest that intact vagus nerve efferents, and the vagal-coeliac-splenic connection are essential for the angiotensin II-induced hypertension.

Importantly, in all hyperthensive animals, splenic denervation prevented splenic CD3+ T-cells to egress to the systemic circulation and reduced the number CD4+ and CD8+ T cells primed to CD44+ (homing) and CD69+ (activation) to infiltrate into the aorta and kidneys.

The study of Carnevale et al. suggests the existence of a new sympathetic mechanism in hypertension. As the authors stated: “sympathetic overactivity in hypertension has effects beyond the kidney and baroreflexes”.

Overall, their study indicates that the cholinergic-sympathetic drive, operating through the vagus-splenic nerve connection, may in turn activate the T cells to migrate to target organs and contribute to blood pressure regulation.

In summary, these results demonstrate that hypertensive challenges exploit a cholinergic-sympathetic drive, realized through a vagus-splenic nerve connection, to activate the T cells that eventually migrate to target organs and contribute to blood pressure regulation.

The authors suggest that selective denervation obtained by thermoablation may have “clinical potential for patients for whom the renal denervation has failed”. On the other hand, they highlight the possibility that the cholinergic anti-inflammatory pathway can be stimulated to prevent severe hypothension, as commonly found during sepsis.

Source: Nat Comm. 2017; 7: 13035. DOI: 10.1038/ncomms13035
Read more: Nature Communications

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