title: Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat.
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.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610. mraizada@ufl.edu or dbaekey@ufl.edu.
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Jun
authors.forename: Seungbum
authors.initials: S
authors.lastname: Kim
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Perez
authors.forename: Aqeela
authors.initials: A
authors.lastname: Afzal
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Shan
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.forename: Monica M
authors.initials: MM
authors.lastname: Santisteban
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Marcelo
authors.initials: M
authors.lastname: Febo
authors.forename: Jay
authors.initials: J
authors.lastname: Mocco
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.forename: Edward
authors.initials: E
authors.lastname: Scott
authors.forename: David M
authors.initials: DM
authors.lastname: Baekey
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001794:Blood Pressure / Q000502:physiology*; D001853:Bone Marrow / Q000294:innervation* / Q000503:physiopathology; D004195:Disease Models, Animal; D006973:Hypertension / Q000503:physiopathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
keywords: EPCs; bone marrow; hypertension; inflammation; rats, inbred SHR; sympathetic drive