Emerging evidence suggests that gut microbiota is critical in the maintenance of physiological homeostasis. The present study was designed to test the hypothesis that dysbiosis in gut microbiota is associated with hypertension since genetic, environmental, and dietary factors profoundly influence both gut microbiota and blood pressure. Bacterial DNA from fecal samples of two rat models of hypertension and a small cohort of patients was used for bacterial genomic analysis. We observed a significant decrease in microbial richness, diversity, and evenness in the spontaneously hypertensive rat, in addition to an increased Firmicutes to Bacteroidetes ratio. These changes were accompanied with decreases in acetate- and butyrate-producing bacteria. Additionally, the microbiota of a small cohort of human hypertension patients was found to follow a similar dysbiotic pattern, as it was less rich and diverse than that of control subjects. Similar changes in gut microbiota were observed in the chronic angiotensin II infusion rat model, most notably decreased microbial richness and an increased Firmicutes to Bacteroidetes ratio. In this model, we evaluated the efficacy of oral minocycline in restoring gut microbiota. In addition to attenuating high blood pressure, minocycline was able to rebalance the dysbiotic hypertension gut microbiota by reducing the Firmicutes to Bacteroidetes ratio. These observations demonstrate that high BP is associated with gut microbiota dysbiosis, both in animal and human hypertension. They suggest that dietary intervention to correct gut microbiota could be an innovative nutritional therapeutic strategy for hypertension.

Rationale Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension (HTN). Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in HTN. Objective Test the hypothesis that pro-inflammatory BM cells from hypertensive animals contribute to neuroinflammation and HTN via a brain-BM interaction. Methods and Results Following BM ablation in spontaneously hypertensive rats (SHR), and reconstitution with normotensive Wistar-Kyoto (WKY) rat BM, the resultant chimeric SHR displayed significant reduction in mean arterial pressure (MAP) associated with attenuation of both central and peripheral inflammation. In contrast, an elevated MAP along with increased central and peripheral inflammation was observed in chimeric WKY rats reconstituted with SHR BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated HTN in both the SHR and chronic angiotensin II (Ang II)-infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic Ang II-infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus (PVN), presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid. Conclusions The BM contributes to HTN by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of HTN. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant HTN therapy.

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.

622( P ro)renin receptor (PRR) is highly expressed in many tissues, including those of the heart and brain, 1,2 and plays an important role in the maintenance of cardiovascular homeostasis in the periphery. 3,4 However, the role of PRR in the brain remains poorly understood. Despite intrinsically low renin concentrations in the brain, the ability of renin to signal in a similar manner to angiotensin (Ang)-II, 5 coupled with the presence of PRR in the brain cardioregulatory areas, 2,6 suggests a role for PRR in central cardiovascular control. Our previous study revealed that PRR expression is significantly increased in the nucleus of the solitary tract (NTS) and the supraoptic nucleus (SON) of spontaneously hypertensive rats (SHR) compared with normotensive Wistar Kyoto (WKY) controls. 6 Genetic knockdown of PRR in the SHR SON 6 and other cardioregulatory regions, such as the subfornical organ (SFO) 7 in hypertensive rats, resulted in a reduction of blood pressure (BP). However, the role of NTS PRR in BP control and its precise mechanisms remain elusive.Our interest in the role of NTS PRR derives from the following: (1) The NTS is the central termination site of baroreceptor input, regulating both the set-point of arterial pressure and the gain of the baroreflex, mechanisms essential for short-and long-term homeostatic control of arterial pressure 8,9 ; (2) In the hypertensive model, the NTS exhibits an abnormal inflammatory state because the expression of many inflammatory mediators known to be involved in modulating synaptic transmission, including interleukin (IL)-6 and C-C motif ligand 5 (Ccl5), are downregulated in the SHR NTS compared with the WKY rats 10,11 ; and (3) PRR mRNA in the SHR NTS is significantly increased compared with the WKY rats. 6 We propose that altered activity of PRR in the NTS is linked to hypertension, and that the NTS PRR regulates BP Abstract-The importance of the (pro)renin receptor (PRR) in the function of the central nervous system is increasingly evident because PRR seems to play a role in neuronal control of cardiovascular function. PRR expression is elevated in the nucleus of the solitary tract (NTS) of spontaneously hypertensive rats (SHR).In this study, we tested the hypothesis that altered activity of PRR in the NTS is linked to hypertension. Eight weeks of chronic knockdown of the NTS PRR, using recombinant adeno-associated virus type 2 (AAV2)-PRR-small hairpain RNA (shRNA)-mediated gene transduction, caused a significant increase in mean arterial pressure (MAP) in the SHR (shRNA, 173±5; Control, 151±6 mm Hg) but not in Wistar Kyoto rats (shRNA, 108±7; Control, 106±6 mm Hg). The MAP elevation in the SHR was associated with decreased inflammatory markers tumor necrosis factor-α, interleukin-6, C-C motif ligand 5, and their transcription factor, nuclear factor-κB. Consistent with the pressor effects of the PRR knockdown, acute bilateral NTS injection of human renin (2 pmol/side) decreased MAP and heart rate (HR) in SHR (ΔMAP, −38±4 mm Hg; Δheart rate, −40±10 bp...

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Decades of evidence have implicated involvement of inflammation in the development and establishment of hypertension (HTN); however, the central mechanisms remain elusive. We propose a hypothesis that dysfunctional bone marrow (BM) activity is critical in HTN, in view of the fact that BM is the predominant source of inflammatory and angiogenic cells. We provide the following evidence in support of this hypothesis: (1) BM from animal models of HTN is proinflammatory. Ablation of the spontaneously hypertensive rat (SHR) BM, and reconstitution with BM from the normotensive Wistar Kyoto (WKY), results in significant reduction in mean arterial pressure (MAP), as well as the decrease in proinflammatory and increase in angiogenic cells in the chimeric SHR; (2) Oral minocycline treatment attenuates MAP, restores autonomic balance, and decreases inflammation in both the SHR and Ang II rat HTN models; (3) Sympathetic nerve activity (SNA) and norepinephrine levels in the BM of the SHR and Ang II rat HTN models are elevated compared to normotensive rats; (4) C57-AdrB1.B2 knock-out (KO) chimera, generated by reconstitution of irradiated C57BL/6J mice with the BM cells of the adrenergic receptor beta 1/2 KO mice (Adrb1tm1Bkk Adrb2tm1Bkk/J), exhibits reduced peripheral inflammatory cell counts. Furthermore, transcriptomics analysis of the BM cells from these chimeric mice revealed significant changes in 67 signaling pathways, thirty-five of which were directly related to modulation of different immune system responses (P<0.01). Most notable were changes in the pathways involved in activation and migration of monocytes and T lymphocytes. These observations demonstrate that BM plays a critical role in regulation of the inflammatory status, and support our hypothesis that dysfunctional BM activity may be an important aspect in the development and establishment of HTN. AHA14SDG18300010.

Increased PRR expression in the NTS of SHR, coupled with the evidence on role of the brain inflammation in cardiovascular functions, has led us to hypothesize that the NTS PRR may play a part in blood pressure (BP) regulation by modulation of the brain inflammatory pathways. Acute NTS injections of renin (0.02–2 pmol) resulted in a significantly greater dose‐dependent decrease in systolic BP (ΔSBP; −12±5 to −32±5 mmHg) and heart rate (ΔHR; −13±7 to −40±10 bpm) in the SHR compared to the WKY rats (ΔSBP: −3±1 to−8±4 mmHg; ΔHR: −2±4 to −12±7 bpm). These effects were not blocked by the AT1R or AT2R blocker. Consistent with this, chronic PRR knockdown with AAV2‐PRR‐shRNA in the SHR NTS caused an increase in mean arterial pressure (shRNA: 173±5; Control: 151±6 mmHg), and decreases in baroreflex bradycardia (shRNA: 0.26±0.04; Control: 0.44±0.04) and parasympathetic tone (shRNA: 31±4; Control: 49±6). This was accompanied by a decrease in the inflammatory markers TNFa, IL6 and Ccl5, and their transcription factors, NF‐κB and AP‐1. Finally, PRR activation in the SHR brain neuronal cultures activated NF‐κB, and increased the mRNA of IL1β (250 fold), TNFα (32 fold), IL6 (35 fold) and Ccl5 (12 fold) in an NF‐κB‐ and AP1‐dependent, but AT1R/AT2R‐independent manner. Therefore, the NTS PRR mediates Ang II‐independent antihypertensive effects by stimulation of NF‐κB/AP‐1/cytokine signaling (AHA 11SDG7420029)

Bone marrow (BM)‐derived endothelial progenitor cell (EPC) contribute to the maintenance of vascular homeostasis and EPC dysfunction is implicated in the vascular pathophysiology in hypertension. Thus, we propose Angiotensin II (Ang II)‐induced neurogenic hypertension is associated with dysfunctional EPC and elevated inflammatory cells (ICs). Ang II infused SD rats (200ng/kg/min, SC, 4–12 weeks) were used to induce hypertension. CD90+/CD4−/5−/8cells were isolated from femur and blood and their functions were assessed. BM and blood EPC decreased by 35% and 70% after 4 and 12 weeks of Ang II infusion, respectively. This was associated with significant increases in BM and blood IC (CD4+/8+/25+, CD3+/45+; CD68+) measured by FACS, leading to significant reduction in EPC/IC. BM EPC migration and proliferation ability toward SDF was reduced by 70±5% at 6 wks, 75±4% at 12 wks, and by 40±3% at 6 wks, 44±5% at 12 wks of Ang II infusion, respectively. Tube formation assay showed endothelial cells from Ang II rats decreased tube length (~25%) and branch numbers (~23%) compared to control. RT‐PCR also showed significant decrease in CXCR4 (~30%) and CXCL12 (~40%) mRNA from 12 weeks Ang II rats. In summary, these data demonstrate EPC/IC is significantly decreased as a result of decreased EPC/increased IC in Ang II induced hypertension. EPC from hypertensive rats are dysfunctional with decreased SDF‐1 and its receptor mRNA.HL33610