Altered Inflammatory Response Is Associated With an Impaired Autonomic Input to the Bone Marrow in the Spontaneously Hypertensive Rat

Abstract

Autonomic nervous system (ANS) dysfunction, exaggerated inflammation and impaired vascular repair are all hallmarks of hypertension. Considering the bone marrow (BM) is a major source of the inflammatory cells (ICs) and endothelial progenitor cells (EPCs), we hypothesized that impaired BM-ANS interaction contributes to dysfunctional BM activity in hypertension. In the SHR, we observed a >30% increase in BM and blood ICs (CD4.8+), and a >50% decrease in EPCs (CD90+.CD4.5.8-) compared to the normotensive Wistar-Kyoto (WKY) rat. Increased tyrosine hydroxylase (70%) and norepinephrine (NE, 160%), and decreased choline acetyl transferase (30%) and acetylcholine esterase (55%) indicated imbalanced ANS in SHR BM. In WKY, night time-associated elevation in SNA (50%) and BM NE (41%) was associated with increased ICs (50%) and decreased EPCs (350%), while BM sympathetic denervation decreased ICs (25%) and increased EPCs (40%). In contrast, these effects were blunted in SHR, possibly due to chronic downregulation of BM adrenergic receptor α2a (by 50-80%) and β2 (30-45%). Application of NE resulted in increased BM IC activation/release, which was prevented by pre-administration of Ach. Electrophysiological recordings of femoral SNA (fSNA) showed a more robust fSNA activity in SHR compared to WKY, peaking earlier in the respiratory cycle, indicative of increased sympathetic tone. Finally, manganese-enhanced magnetic resonance imaging (MEMRI) demonstrated that pre-sympathetic neuronal activation in SHR was associated with an accelerated retrograde transport of the GFP-labeled pseudorabies virus from the BM. These observations demonstrate that a dysfunctional BM ANS is associated with imbalanced EPCs and ICs in hypertension.

Arterial Stiffness: Pathophysiological and Genetic Aspects

“…Recent studies have shown that increased arterial stiffness associated with aging is closely related to increased sympathetic nerve activity 36 and, consequently, exacerbation of the inflammatory process. 37 It is important to note that the chronic diseases most associated with increased PWV (diabetes, hypertension and obesity itself) have an underlying inflammatory component. Thus, the PWV measurement could represent the clinical sentinel monitoring the chronic inflammatory process in these conditions.…”

Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure

“…We have recently suggested a direct role for inflammatory BM cells in the pathophysiology of hypertension (HTN) in rodent models that present with this condition (13,24,35). More specifically, we observed a significant increase in BP in the normotensive Wistar-Kyoto (WKY) rat strain following a full ablation and reconstitution of their IS with BM cells derived from spontaneously hypertensive rats (SHRs) (24).…”

“…Activation of the BM beta 1 and 2 adrenergic receptors, in particular, has been shown to modulate the levels of different immune cells in circulation, with inflammatory cells predominantly released during the highest activity period [i.e., night time in rodents and day time in humans (5, 9, 17, 18, 25)], an evolutionary mechanism developed to prime the system for warding off infection, should the need arise. On the other hand, the reciprocal action of an activated IS on the CNS has also been suggested, with significant evidence for the role of an exaggerated IS in diseases of the cardiovascular system (CVDs) as well as metabolic diseases such as diabetes and obesity (3,12,24,27).We have recently suggested a direct role for inflammatory BM cells in the pathophysiology of hypertension (HTN) in rodent models that present with this condition (13,24,35). More specifically, we observed a significant increase in BP in the normotensive Wistar-Kyoto (WKY) rat strain following a full ablation and reconstitution of their IS with BM cells derived from spontaneously hypertensive rats (SHRs) (24).…”

“…Moreover, we recently observed an increase in the BM SNS activity in the SHRs, which may contribute to both the aberrant adrenergic receptor expression in the BM of SHR, as well as the apparent dysfunction in the diurnal release pattern of the BM cells into the circulation, leading to chronically elevated systemic levels of inflammatory cells in the SHRs (35). Con-sidering the significant role of an overactive SNS in HTN (7,26,35), and in light of the aforementioned evidence, we hypothesized that BM adrenergic receptor signaling, particularly the beta 1 and 2 adrenergic receptors, play a major role in the modulation of the BM inflammatory response, which in turn regulates BP.…”

“…Con-sidering the significant role of an overactive SNS in HTN (7,26,35), and in light of the aforementioned evidence, we hypothesized that BM adrenergic receptor signaling, particularly the beta 1 and 2 adrenergic receptors, play a major role in the modulation of the BM inflammatory response, which in turn regulates BP. To test this hypothesis, we generated a novel mouse BM chimera model, in which the ablated BM was fully reconstituted with BM derived from the beta 1 and 2 adrenergic receptor knockout (KO) mice.…”