title: Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.
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 O(2)(-·), 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.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Jun
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.forename: Aqeela
authors.initials: A
authors.lastname: Afzal
authors.forename: Jessica Marulanda
authors.initials: JM
authors.lastname: Carvajal
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000831:Animals, Newborn; D001341:Autonomic Nervous System / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D057967:Infusions, Intraventricular; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D000804:Angiotensin II; D049452:Green Fluorescent Proteins