Abstract P409: Angiotensin Ii Activates At1a Receptors In Sfo-pvn-dmv To Modulate The Autonomic Nervous System And Immune System In Hypertension

Angiotensin II (AngII) modulates the autonomic nervous system (ANS) and we have previously found that it activates a vagal-splenic reflex that in turn promotes lymphocytes priming and blood pressure increase. AngII binds type 1a receptors (AT1aR) expressed in the neuronal centers of the cardiovascular control, among which the dorsal motor nucleus of the vagus nerve (DMV). Here we hypothesize that AngII signaling in the DMV activates the vagal-splenic pathway elicited by hypertension. To investigate whether circulating AngII targets the DMV, we intravenously injected fluorescent AngII in mice implanted with osmotic minipumps (AngII or veh), finding it in the DMV complex of AngII mice . To target DMV AT1aR signaling, we utilized AT1aRflox crossed with mice expressing cre-recombinase in PHOX2B neurons. We verified gene deletion by RNAscope and infused AngII, finding no protection from HTN (SBP 147±4 vs 146±2 mmHg in AT1aR-KO-DMV vs WT, p=0.797). Hence we investigated whether upstream brain areas relevant for AngII signaling, the paraventricular nucleus of the hypothalamus (PVN) and the subfornical organ (SFO), modulate DMV complex. Interestingly, AngII was able to cross BBB of PVN and SFO of hypertensive mice. Mechanistically, we targeted AT1aR gene in PVN and SFO, finding protection from AngII-HTN in both cases (SBP 109±1 vs 144±1 mmHg in AT1aR-KO-PVNvsWT, p<0.001; SBP 140±2 vs 160±2 mmHg, in AT1aR-KO-SFOvsWT, p<0.001). Consequently, to test whether the SFO might be the first sensor of hypertension-induced vagus-splenic activity, we measured the SSNA in AT1aR- SFO KO finding it significantly reduced (107±10vs323±57 in AngII AT1aR-SFO KOvsWT, as number of spikes by microneurography, p<0.01), as immune cell egression was (splenic CD3+area 120±10 vs 64±7 mm 2 *10 3 in AngII AT1aR-SFO KOvsWT, p<0.001). These results suggest that AT1aRs in the SFO-PVN axis modulates the DMV function and in turn the vagal-splenic reflex in HTN.