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 (PVN) of the hypothalamus, is driven by mitochondrial reactive oxygen species (ROS) and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II (Ang II) infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the PVN. This was associated with 46% decrease in BM EPCs and 250% increase in BM ICs, resulting in 5 fold decrease of EPCs/ICs ratio in the BM. Treatment with mitoTEMPO, a scavenger of mitochondrial O2−• intracerebroventricularly but not subcutaneously, attenuated Ang II-induced hypertension, decreased activation of microglia in the PVN, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with GFP-tagged pseudorabies virus (PRV). Administration of GFP-PRV into the BM resulted in predominant labeling of PVN neurons within 3 days, with some fluorescence in the NTS, RVLM and SFO. Taken together, these data demonstrate that inhibition of mitochondrial ROS attenuates Ang 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.

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

“…Furthermore, these mice have no reported differences in hematopoiesis. Mice were euthanized, and the whole BM was extracted by established methods (13,24,35). Whole BM cells from AdrB1 tm1Bkk AdrB2 tm1Bkk /J mice were reconstituted to near lethally irradiated (x-ray, 950 Rad) 6 wk old male C57BL/6J mice by a single retro-orbital injection at a ratio of 1:4 (donor-recipient), to generate the BM AdrB1.B2 KO chimera mice.…”

“…Blood was collected from all mice at night time (8:00 PM), corresponding to the period of highest sympathetic drive (35), to compare its effects on the BM-derived circulating inflammatory and endothelial progenitor cells in C57 and AdrB1.B2 KO chimera mice. For fluorescence-activated cell sorting (FACS), MNCs from blood were prepared in a concentration of 0.5-1 ϫ 10 6 cells/100 l of PBS ϩ 2% FBS ϩ 1 mM EDTA medium, as previously described (13,24,35). Circulating CD4 ϩ cells were used as representative markers of T cells (antibody purchased from Biolegend, cat.…”

“…Mice were euthanized, and the femoral whole BM was collected from AdrB1.B2 KO and control C57 chimera mice by established methods (13,24,35). For isolation of MNCs from the BM, femoral bones were collected into MNC isolation buffer (PBS ϩ 2% FBS ϩ 1 mM EDTA buffer).…”

“…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).…”