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SNS driven hypertension enhances hematopoiesis
gests that the improvements in plaque size and complexi- ty are due to dampened myelopoiesis and, subsequently, reduced monocyte infiltration.
Discussion
Chronic hypertension is arguably one of the most com- mon risk factors associated with atherosclerotic CVD.1 However, delving into the responsible mechanism(s), it remains unclear if an increase in blood pressure alone, or in conjunction with a change in concurrent signaling events such activation of the RAS or sympathetic activa- tion, directly contributes to atherosclerotic CVD. Using a genetic model of hypertension driven by sympathetic acti- vation, we show that this form of hypertension (com- pared to atherosclerotic prone mice without hypertension) alters the characteristics of the atherosclerotic lesion to a more unstable phenotype, hallmarked by increased macrophage accumulation. We also found that chronic sympathetic activation caused changes in hematopoiesis. In particular, increased sympathetic activity was found in the BM, altering the HSPC microenvironment and causing the liberation of certain stem cells to the spleen where monocytes were generated. This was accompanied by an increase in blood monocytes, likely explaining the increased macrophage burden observed in the atheroscle- rotic lesions. These atherogenic pathways could all be inhibited pharmacologically by blocking sympathetic sig- nalling through b-adrenoreceptors using propranolol. These findings suggest that chronic sympathetic activa- tion, present in many forms of hypertension, likely con- tributes to the increased CVD risk by modulating hematopoiesis, independent of endothelial dysfunction.
With respect to understanding the contribution of hypertension to vascular disease, the majority of research has focused on the effects on the endothelium. Perhaps the most common belief is that hypertension causes endothelial dysfunction and activation, which in turn recruits immune cells and forms the main mechanism propagating the atheroma. Interestingly, we found no evi- dence of endothelial dysfunction in our hypertensive mice, at least in this model of a dominant sympathetic driven form of hypertension, the endothelial dysfunction was not contributing significantly to atherogenisis.34 Supporting our theory that underlying sympathetic nerv- ous signaling, that may be independent of pressure itself, can drive atherogenesis, moderate increases in AngII are sufficient to promote accelerated atherogenesis, without elevations in blood pressure.3,4 Additionally, AngII has also been shown to invoke a T-helper cell (TH1) immune response to promote atherogenesis independent of its hemodynamic effects. Thus, signaling events that can cause hypertension are likely important in driving CVD through their immune modulatory responses.7-10,35,36 Further, with the discovery of accelerated vascular disease driven by acute events triggering sympathetic activation leading to enhanced monocyte production, it is plausible that this pathway is triggered in chronic SNS-driven hypertension and would contribute to accelerated athero- sclerosis.21,23,24 We hypothesized that the overactive SNS seen in subgroups of patients with hypertension would contribute to atherogenesis by stimulating hematopoiesis. Importantly, elevated WBCs are associated with the inci- dence of hypertension and predicts CV outcomes in this
patient group.37-39 However, the cause of increased WBCs in hypertensive patients has not been resolved.
Consistent with recent studies which have observed monocytosis following acute scenarios of sympathetic activation, we too observed monocytosis in the hyperten- sive BPH/Apoe-/- mice.21,24 The initial predominant change driven by the overactive sympathetic signaling in our study, relevant to increased myelopoiesis, appears to occur within the BM. We noted a decreased abundance of two key niche cells, endothelial cells and osteoblasts, which harbour anchoring points in the marrow for HSPCs, preventing their release into circulation.40-43 The contribution of the SNS in regulating this process was first described by a seminal study from the Frenette laboratory, detailing the requirement of a functional SNS in the BM, which is required for G-CSF mediated HSPC mobiliza- tion.16 Almost a decade later, the Nahrendorf group discov- ered the importance of this pathway in respect to CVD, revealing that sympathetic activation following an acute myocardial infarction promotes HSPC liberation to the spleen where the production of an additional atherogenic pool of monocytes occurs.21 The absence of an expanded HSPC population in the spleen is likely due to the chronic nature of our study and suggests that these cells likely rap- idly matured into myeloid committed progenitors. The recent studies then suggest that the monocytes generated, migrated into the atherosclerotic lesion, and enhanced macrophage burden, potentiating the risk of a secondary CV event. Our data reveal that this process is occurring chronically and identifies an important mechanism that likely contributes to atherogenesis and the increased risk of a CV event in hypertension. We also identified another pathway by which sympathetic signaling can induce the liberation of BM HSPCS by causing a decrease in the HSPC-expressed retention receptor CXCR4. Given that HSPCs do not appear to express b adrenoreceptors, it sug- gested a cell extrinsic mechanism resulting in less HSPC cell surface CXCR4. Interestingly, neutrophils express b2 adrenoceptors and can be activated after sensing NE (Online Supplementary Figure S2, B-C). Modelling this in vitro revealed that NE-activated neutrophils produce MMP9, which cleaves CXCR4 on HSPCs. Thus, BM sym- pathetic activation likely liberates HSPCs via multiple mechanisms, some of which are independent of the previ- ously described SNS/G-CSF axis.
As mentioned above, there are several studies that have identified a role for b adrenoreceptors in influencing HSPC release via modulating the BM niche. There is strong evi- dence for the role of b-3 adrenergic receptor in regulating nestin+ stromal cell production of key factors such as CXCL12, angiopoietin and stem cell factor, thereby influ- encing HSPC retention and proliferation. b-3 antagonism following ischemic events has shown reduced HSPC mobilisation and proliferation leading to dampened extramedullary hematopoiesis.19,21,23,24 However, there is also strong evidence pointing to a role for the b-2 adrener- gic receptor in regulating BM niche components and HSPC mobilisation. Although this has been suggested to occur through other niche components such as osteoblasts and other stromal cells and not specifically nestin+ cells.16,18 These findings regarding the role of b adrenocep- tors in modulating HSPC mobilisation suggest that in our study there is a likely contribution of both b-2 and b-3 receptors to changes in the BM. However, considering the role of b-2 in the setting of hypertension and elevated
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