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

Author:

Zubcevic Jasenka1,Jun Joo Yun1,Kim Seungbum1,Perez Pablo D.1,Afzal Aqeela1,Shan Zhiying1,Li Wencheng1,Santisteban Monica M.1,Yuan Wei1,Febo Marcelo1,Mocco Jay1,Feng Yumei1,Scott Edward1,Baekey David M.1,Raizada Mohan K.1

Affiliation:

1. From the Department of Physiology and Functional Genomics, College of Medicine (J.Z., J.Y.J., S.K., Z.S., M.M.S., W.Y., E.S., M.K.R.), Department of Psychiatry, College of Medicine (P.D.P., M.F.), and Department of Physiological Sciences (D.M.B.), University of Florida, Gainesville; Department of Neurological Surgery, Vanderbilt University, Nashville, TN (A.A., J.M.); and Department of Biomedical Science, Colorado State University, Fort Collins (W.L., Y.F.).

Abstract

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

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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