Hypothalamic Regulation of Blood Pressure

Abstract

In addition to brainstem nuclei well‐known to be involved in baroreflex regulation of blood pressure, several hypothalamic regions have also been shown to modulate autonomic regulation and cardiovascular function. Among them, the paraventricular nucleus (PVN) comprised of magnocellular neurons involved in vasopressin and oxytocin secretion and parvocellular neurons involved in pre‐sympathetic activity. Elevated firing activity of pre‐sympathetic PVN neurons is thought to contribute to hypertension. The PVN also contains components of the renin‐angiotensin system (RAS), like the angiotensin‐II type 1 receptor (AT1R) which expression is enhanced in hypertensive conditions. We previously reported that Angiotensin converting enzyme 2 (ACE2) is also expressed in the PVN and capable of metabolizing Ang‐II levels thus reducing Ang‐II pro‐hypertensive signaling. More recently, we identified ADAM17 as a critical mediator of AT1R downstream signaling, supporting the maintenance of hypertension and neuro‐inflammation. We observed that during RAS overactivity, AT1R stimulation leads to translocation of ADAM17 from the cytoplasm to the plasma membrane, leading to enhanced activity of this sheddase. As a result, ACE2 is cleaved by ADAM17 from the plasma membrane and the compensatory activity of the enzyme is thus compromised, promoting an imbalance of autonomic function and favoring the development of neurogenic hypertension. Recently, we investigated the interaction of AT1R, ADAM17 and ACE2 on PVN pre‐sympathetic neurons and hypothesized that ADAM17 would impair ACE2 regulation of neuronal activity on these cells, leading to an increase in sympathetic outflow and eventually blood pressure. We also attempted to identify patterns of expression for these RAS components on specific PVN neurons. To address these questions, we relied on novel transgenic mouse models with selective deletion of RAS components in the PVN and electrophysiology. Our observations suggest that ACE2 maintains inhibitory neurotransmission into the PVN and its expression is prevalent on inhibitory neurons. On the other hand, ADAM17 is critical for Ang II‐mediated activation of kidney‐related presympathetic glutamatergic neurons in the PVN, confirming the supportive role of ADAM17 in increasing presympathetic neuronal activity. Balancing inhibitory and excitatory neurotransmission from the PVN is essential to prevent a sympathetic overdrive and our observations provide new targets to modulate excessive sympathetic activity in hypertension.Support or Funding InformationNHLBI HL093178.