Neurogenic hypertension is characterized by elevated sympathetic activity which exacerbates end organ failure in human and animal models. Angiotensin II (AngII), a major culprit in neurogenic hypertension, acts through the activation of AT1 receptors to evoke increased sympathetic activity within areas in the central nervous system that plays critical role in cardiovascular regulation, such as the paraventricular nucleus (PVN) and the rostral ventrolateral medulla (RVLM). However, the mechanism by which AngII acts on these areas is not completely understood. Based on our data, we propose here a novel mechanism, involving blood brain barrier (BBB) disruption, by which circulating AngII is able to access these brain regions, contributing in turn to sympathoexcitation in neurogenic hypertension. In addition, AngII plays a crucial role mediating inflammation through oxidative stress and microglia activation during hypertension. Still, the underlying mechanism and pathways by which AngII promotes inflammation, and whether this is linked to BBB disruption, is yet unknown. Recent evidence supports toll like receptor 4 (TLR4), an essential component of the innate immune response, in AngII-mediated inflammatory responses. Moreover, our preliminary data shows upregulation of TLR4 in the brain of spontaneously hypertensive rats (SHR), as well as its association with microglial activation and reactive oxygen species (ROS) production. Given this, we propose microglial TLR4 to be a pivotal molecular link causally connecting AngII-mediated microglial cell activation, oxidative stress and BBB disruption in hypertension. To test this hypothesis, the following specific aims are proposed: 1) To determine whether AngII-AT1rs results in overexpression and activation of microglial TLR4 receptors within the PVN/RVLM of SHRs, leading to an active, proinflammatory microglial cell state; 2) To evaluate whether the AngII-AT1r-TLR4 signaling cascade in PVN/RVLM microglial cells results in production of ROS in SHRs and 3) To assess whether microglia-TLR4 contributes to AngII-mediated BBB disruption in SHRs. A combination of in vitro and in vivo approaches are proposed to answer these questions. We expect results from this work to enhance our understanding of the interrelationship between AngII and the brain immune system (microglial TLR-signaling) in increased brain inflammation and sympathoexcitation during hypertension.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2014 → 06/30/2018|