Arterial blood pressure is controlled by the autonomic division of the central nervous system. Dysregulations in this control can produce hypertension or hypotension. Both conditions can damage major organs and pose a significant threat to human health. The mechanisms underlying blood pressure control are still under investigation. Recent studies have indicated a potential role for two non-neuronal glial cells, astrocytes and microglia, in the autonomic control of blood pressure.
Glia can have powerful effects on neuronal activity which can in turn have profound physiological consequences. The mechanisms underlying glia-neuron communication, and the resulting effects on blood pressure control, are largely unexplored. In general terms, astrocytes can modulate neuronal activity by affecting their electrochemical properties, while microglia can exert control of neuronal properties via inflammation. This thesis investigated the role of microglia, the immune cells of the central nervous system, in the autonomic control of blood pressure. This role was considered in the context of two major pathologies: neurogenic hypertension and septic hypotension.
In Chapter 3, alterations were found in the microglia of spontaneously hypertensive rats (SHR) compared to the control strain, Wistar-Kyoto rats (WKY). The microglia of SHR had reduced expression of two key receptors: the ATP/ADP receptor P2Y12R and the fractalkine receptor CX3CR1. This occurred specifically in the rostral ventrolateral medulla (RVLM), a crucial brainstem region controlling arterial blood pressure. The SHR RVLM also contained fewer microglia than the RVLM of control rats, and these microglia had shorter branches, indicating a change in cellular activity.
Chapter 4 assessed the effects of hypotension, hypertension, and peripheral inflammation on inflammation in the rat brain. A low dose of the endotoxin lipopolysaccharide (LPS) delivered systemically caused a small downregulation of P2Y12R in the brain, as well as an upregulation of pro- inflammatory molecules. Other gene expression changes were found in cardiovascular regions of the brainstem and midbrain in SHR. Hypotension alone was not sufficient to produce an inflammatory effect in the brain.
In Chapter 5, peripheral administration of LPS produced hypotension in rats, recapitulating a major autonomic effect of septic shock. Although LPS did not affect microglial morphology in this model, central application of the specific P2Y12R antagonist PSB0739 reduced the number of process branches and endpoints in microglia at the ventral surface of the medulla.
Chapter 6 continued the model of LPS-induced hypotension by pharmacologically inhibiting TLR4, the main signal-transducing receptor for LPS, with TAK242 (also known as Resatorvid). Peripheral TLR4 inhibition, but not central TLR4 inhibition, attenuated LPS-induced hypotension in rats. As with the work described in Chapter 5, LPS did not produce a morphological change in microglia in the ventral medulla. Additionally, central or peripheral TLR4 inhibition did not affect microglial morphology.
Overall, this thesis demonstrated a role for microglia in chronic hypertension, but not in acute blood pressure changes or peripheral inflammation.