Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension

Abstract

Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+ T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+ cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN. NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.

Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve

“…Three weeks after viral injections in nodose ganglia, we performed direct electrophysiological recordings of afferent vagal activity rostral to both LNG and RNG simultaneously using a modified decorticated artificially perfused rat (DAPR) in situ preparation 2 weeks following viral injections in nodose ganglia. The modification to the previously described DAPR [33][34][35] included retention of an intact GI tract with a separate perfusion system allowing specific targeting of GI vagal afferents by delivering ghrelin or CCK via arterial GI circulation (see schematics of the modified in situ DAPR in Figure 2A). Wistar rats (male, 6 weeks old, 100-120 g, n = 8) were briefly anesthetized with isoflurane (4%), exsanguinated, decorticated (decerebrated at the precollicular level as originally described in [36]), and immediately submerged into ice-chilled artificial cerebrospinal fluid (aCSF; composition in mM: 125 NaCl, 24 NaHCO3, 3KCl, 2.5 CaCl2, 1.25 MgSO4 and 1.25 KH2PO4, 10 dextrose, pH 7.3) (Sigma-Aldrich and Fisher, USA).…”

“…Simultaneous recordings of the left and right afferent nerve activity (LNG and RNG; Figure 2A) were obtained using glass suction electrodes (tip diameter, 0.2-0.3 mm), amplified (20-50K) and filtered (3-30K), sampled at 5 kHz (CED, Cambridge) and monitored using Spike2 (CED). The perfusate flows (19-24 mL/min for brainstem and 1.5-3.5 mL/min for GI perfusion) were adjusted to mimic physiologic perfusion levels and maintain the health of the preparation [33][34][35]37]. Vasopressin (1.25-4 nM final concentration, Sigma-Aldrich, USA) was added to the brainstem perfusate to increase vascular resistance and aid in maintenance of adequate brainstem perfusion to preserve autonomic reflexes [33][34][35].…”

“…The perfusate flows (19-24 mL/min for brainstem and 1.5-3.5 mL/min for GI perfusion) were adjusted to mimic physiologic perfusion levels and maintain the health of the preparation [33][34][35]37]. Vasopressin (1.25-4 nM final concentration, Sigma-Aldrich, USA) was added to the brainstem perfusate to increase vascular resistance and aid in maintenance of adequate brainstem perfusion to preserve autonomic reflexes [33][34][35]. Bilateral vagal afferent responses were simultaneously recorded in response to slow bolus intra-arterial GI infusion of 1) saline (0.9%, 100 ml), 2) ghrelin (Phoenix Peptide, 031-31, 5nmol in 100 ml saline), and 3) CCK (Bachem, Cat# 4033010, 1 mg in 100 mL saline) within each preparation, always in this order.…”

The importance of bone marrow and the immune system in driving increases in blood pressure and sympathetic nerve activity in hypertension

“…Human T lymphocytes can also reportedly produce components of the renin–angiotensin system, and this activity is enhanced, in a feedforward manner, with exposure to Ang II (Coppo et al., 2008). Recent research found that serum complement 3, a central hub of the complement IS, is elevated in prehypertensive patients (Bao et al., 2017), and elevated IS markers have also been demonstrated before development of HTN in rodent models (Ahmari et al., 2019; Santisteban et al., 2017), suggesting possible causation. Indeed, infusion of activated lymphocytes in patients with metastatic melanoma has been found to increase BP (Balsari et al., 1986).…”

Ghrelin signaling regulates feeding behavior, metabolism, and memory through the vagus nerve

“…Three weeks after viral injections in nodose ganglia, we performed direct electrophysiological recordings of afferent vagal activity rostral to both LNG and RNG simultaneously using a modified decorticated artificially perfused rat (DAPR) in situ preparation 2 weeks following viral injections in nodose ganglia. The modification to the previously described DAPR [58][59][60] included retention of an intact GI tract with a separate perfusion system allowing specific targeting of GI vagal afferents by delivering ghrelin or CCK via arterial GI circulation (see schematics of the modified in situ DAPR in Fig. 2A).…”