Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (−11±2 mm Hg) and CGX (−11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (−5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (−10±5 mm Hg) compared with baseline control (−25±10 mm Hg). This was not the case in mice in the SHAM (day 10; −28±5 mm Hg) or CGX (day 10; −34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Abstract 19932: A Neuroimmune Drive Activates Plgf to Control an Epigenetic Mechanism in the Spleen That Allows T Cells Activation in Hypertension

Introduction and Hypothesis: In the past several years, there has been mounting interest in the roles played by immunity in hypertension. However, where and how the immune system gets activated under hypertensive stimuli to contribute to hypertension, is still enigmatic. The activation of effector T cells in hypertension suggests that antigen presentation by a specialized subset of innate cells represents an important component that participates in this process. In particular, it has been recently shown that T cell costimulation by B7 ligands is an important mechanism in the development of hypertension. Methods and Results: Here we demonstrate a novel splenic mechanism driven by Placental Growth Factor (PlGF) and regulating T cells costimulation in AngII-induced hypertension. We have found that PlGF is necessary to allow CD86 expression, crucial in AngII hypertension. Moreover, we show that this effect is exerted by a Sirt1-dependent epigenetic modulation of Timp3 expression in splenic macrophages, obtained by controlling p53 repressor activity on its promoter. Since the brain plays a pivotal role in AngII-induced hypertension and it is known that a selective removal of sympathetic innervation to the splanchnic district, obtained by celiac ganglionectomy (CGX), markedly attenuated hypertension, we looked whether the early induction of splenic PlGF upon AngII could be mediated by a nervous drive. Indeed, when we performed CGX in WT mice, splenic PlGF was markedly reduced, thus demonstrating that is is activated by Ang-II induced SNS overactivity. Importantly, we show that this neuroimmune mechanism driven by PlGF is crucial for the onset of hypertension, since PlGF KO mice display a clear-cut protection from the typical AngII-hypertensive response and from T cells infiltration in vessels and kidneys. Finally, chimeric mice generated by spleen transplantation (PlGF KO spleen in WT background and vice versa), allowed us to finally demonstrate that PlGF is indispensable in the spleen for the onset of hypertension. Conclusions: Summarizing, our study brought to light both how important the neuroimmune drive in the spleen is in the genesis of hypertension and, at same time, unveil that PlGF is the molecular pathway recruited in the spleen to control BP raising.

Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension

We previously reported that mild deoxycorticosterone acetate (DOCA)-salt hypertension develops in the absence of generalized sympathoexcitation. However, sympathetic nervous system activity (SNA) is regionally heterogeneous, so we began to investigate the role of sympathetic nerves to specific regions. Our first study on that possibility revealed no contribution of renal nerves to hypertension development. The splanchnic sympathetic nerves are implicated in blood pressure (BP) regulation because splanchnic denervation effectively lowers BP in human hypertension. Here we tested the hypothesis that splanchnic SNA contributes to the development of mild DOCA-salt hypertension. Splanchnic denervation was achieved by celiac ganglionectomy (CGX) in one group of rats while another group underwent sham surgery (SHAM-GX). After DOCA treatment (50 mg/kg) in rats with both kidneys intact, CGX rats exhibited a significantly attenuated increase in BP compared with SHAM-GX rats (15.6 ± 2.2 vs. 25.6 ± 2.2 mmHg, day 28 after DOCA treatment). In other rats, whole body norepinephrine (NE) spillover, measured to determine if CGX attenuated hypertension development by reducing global SNA, was not found to be different between SHAM-GX and CGX rats. In a third group, nonhepatic splanchnic NE spillover was measured as an index of splanchnic SNA, but this was not different between SHAM (non-DOCA-treated) and DOCA rats during hypertension development. In a final group, CGX effectively abolished nonhepatic splanchnic NE spillover. These data suggest that an intact splanchnic innervation is necessary for mild DOCA-salt hypertension development but not increased splanchnic SNA or NE release. Increased splanchnic vascular reactivity to NE during DOCA-salt treatment is one possible explanation.

Effect of mesenteric vascular congestion on reflex control of renal blood flow

Portal hypertension initiates a splenorenal reflex, whereby increases in splenic afferent nerve activity and renal sympathetic nerve activity cause a decrease in renal blood flow (RBF). We postulated that mesenteric vascular congestion similarly compromises renal function through an intestinal-renal reflex. The portal vein was partially occluded in anesthetized rats, either rostral or caudal to the junction with the splenic vein. Portal venous pressure increased (6.5 ± 0.1 to 13.2 ± 0.1 mmHg; n = 78) and mesenteric venous outflow was equally obstructed in both cases. However, only rostral occlusion increased splenic venous pressure. Rostral occlusion caused a fall in RBF (−1.2 ± 0.2 ml/min; n = 9) that was attenuated by renal denervation (−0.5 ± 0.1 ml/min; n = 6), splenic denervation (−0.2 ± 0.1 ml/min; n = 11), celiac ganglionectomy (−0.3 ± 0.1 ml/min; n = 9), and splenectomy (−0.5 ± 0.1 ml/min; n = 6). Caudal occlusion induced a significantly smaller fall in RBF (−0.5 ± 0.1 ml/min; n = 9), which was not influenced by renal denervation (−0.2 ± 0.2 ml/min; n = 6), splenic denervation (−0.1 ± 0.1 ml/min; n = 7), celiac ganglionectomy (−0.1 ± 0.3 ml/min; n = 8), or splenectomy (−0.3 ± 0.1 ml/min; n = 7). Renal arterial conductance fell only in intact animals subjected to rostral occlusion (−0.007 ± 0.002 ml·min−1·mmHg−1). This was accompanied by increases in splenic afferent nerve activity (15.0 ± 3.5 to 32.6 ± 6.2 spikes/s; n = 7) and renal efferent nerve activity (32.7 ± 5.2 to 39.3 ± 6.0 spikes/s; n = 10). In animals subjected to caudal occlusion, there were no such changes in renal arterial conductance or splenic afferent/renal sympathetic nerve activity. We conclude that the portal hypertension-induced fall in RBF is initiated by increased splenic, but not mesenteric, venous pressure, i.e., we did not find evidence for intestinal-renal reflex control of the kidneys.