PROJECT 1 (Davisson): Hypertension and prostanoid signaling in the subfornical organ of the brain There is compelling evidence that human hypertension is characterized by neurohumoral dysfunction, and inappropriate angiotensin II (Angll) signaling in the CNS is a primary culprit. The subfornical organ (SFO), a forebrain structure considered a key "gateway" to the CNS for circulating Angll, provides extensive inputs to the paraventricular nucleus (PVN) and its output neurons mediating sympathetic activation and release of hormones, e.g., vasopressin. Our work shows that excessive reactive oxygen species (ROS) signaling in SFO are critical in "slow-pressor" Angll hypertension, a subpressor Angll infusion model that recapitulates critical features of essential hypertension. However, the signaling mechanisms within the SFO by which Angll and oxidant products initiate the neurohumoral dysfunction leading to the blood pressure elevation are not clear. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E2 (PGE2), have long been implicated in the signaling pathways of Angll, but their role in critical mechanisms in the SFO underlying slow-pressor Angll hypertension has not been elucidated. Our preliminary data suggest a crucial role of COX-1-derived PGE2 acting on PGE2 EP1 receptors (EP1R) in Angll slow pressor hypertension. Project 1 will test the central hypothesis that PGE9 provides an essential link between Angll, ROS and the maladaptive changes that occur in the SFO-PVN axis which lead to neurohumoral dysfunction in the Ang-ll slow-pressor model.
Aim 1 will test the hypothesis that AT, receptors, NADPH oxidase subunits and PGE2-related molecules are co-localized in PVN-projecting SFO neurons in a manner consistent with their functional interaction.
Aim 2 will test the hypothesis that administration of slow pressor doses of Angll elicits C0X1- dependent PGE2 production in the SFO.
This aim will also determine whether ROS production is upstream or downstream of PGE2.
Aim 3 will use single-cell electrophysiology and ROS imaging to test the hypothesis that COX-1-derived PGE2 is required for the enhancement of Ca2+ currents and ROS production induced by Angll in PVN-projecting SFO neurons.
Aim 4 will test the hypothesis that EPiR in SFO are necessary and sufficient to confer susceptibility to slow-pressor Angll neurohumoral dysfunction and hypertension. We will use a newly developed conditional EP1R null mouse in which EP1R expression can be regionally reconstituted by local delivery of Cre recombinase.
Hypertension has devastating effects on the brain, and the brain, in turn, is a primary culprit in driving the neurohumoral dysfunction that leads to hypertension. This research has the potential to fundamentally advance our understanding of the molecular mechanisms linking the CNS with cardiovascular disease, and could have important implications for novel therapeutic approaches targeting the neurogenic component of hypertension and its cardiovascular and cerebrovascular complications.
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