Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension

Joo Yun Jun, Jasenka Zubcevic, Yanfei Qi, Aqeela Afzal, Jessica Marulanda Carvajal, Jeffrey S. Thinschmidt, Maria B. Grant, J. Mocco, Mohan K. Raizada

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O2, intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension.

Original languageEnglish (US)
Pages (from-to)1316-1323
Number of pages8
JournalHypertension
Volume60
Issue number5
DOIs
StatePublished - Nov 2012
Externally publishedYes

Fingerprint

Angiotensin II
Paraventricular Hypothalamic Nucleus
Bone Marrow
Blood Vessels
Hypertension
Brain
Suid Herpesvirus 1
Microglia
Green Fluorescent Proteins
Bone Marrow Cells
Reactive Oxygen Species
Oxidative Stress
Subfornical Organ
Solitary Nucleus
Baroreflex
Hypothalamus
Antioxidants
Fluorescence
Endothelial Progenitor Cells
Blood Pressure

Keywords

  • endothelial progenitor cells
  • mean arterial pressure
  • mitochondrial reactive oxygen species
  • neurogenic hypertension

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Jun, J. Y., Zubcevic, J., Qi, Y., Afzal, A., Carvajal, J. M., Thinschmidt, J. S., ... Raizada, M. K. (2012). Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. Hypertension, 60(5), 1316-1323. https://doi.org/10.1161/HYPERTENSIONAHA.112.199547

Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. / Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S.; Grant, Maria B.; Mocco, J.; Raizada, Mohan K.

In: Hypertension, Vol. 60, No. 5, 11.2012, p. 1316-1323.

Research output: Contribution to journalArticle

Jun, JY, Zubcevic, J, Qi, Y, Afzal, A, Carvajal, JM, Thinschmidt, JS, Grant, MB, Mocco, J & Raizada, MK 2012, 'Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension', Hypertension, vol. 60, no. 5, pp. 1316-1323. https://doi.org/10.1161/HYPERTENSIONAHA.112.199547
Jun, Joo Yun ; Zubcevic, Jasenka ; Qi, Yanfei ; Afzal, Aqeela ; Carvajal, Jessica Marulanda ; Thinschmidt, Jeffrey S. ; Grant, Maria B. ; Mocco, J. ; Raizada, Mohan K. / Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. In: Hypertension. 2012 ; Vol. 60, No. 5. pp. 1316-1323.
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