Abstract 132: Obesity-Related Hypertension Develops Through Splenic Sympathetic Overactivity and is Mediated by Immune-Modulating Functions of Placental Growth Factor

Abstract

Obesity-related hypertension (HTN) is an epidemic health problem and a major risk factor for the development of cardiovascular disease. A consistent amount of research on the pathophysiological basis of obesity has implicated a crucial role of sympathetic overdrive. Interestingly, an overactivation of the sympathetic nervous system (SNS) accompanies HTN as well. Recent data highlighted that increased SNS activation in HTN is important in modulating immune responses, besides controlling typical cardiovascular functions. Whether neuroimmune mechanisms are relevant in obesity-induced HTN is still unknown. To test this hypothesis we subjected 6 week-old C57Bl/6J mice to high fat diet (HFD), as compared to low fat diet (LFD) and monitored blood pressure (BP), which started to rise after 2 months and steadily increased up to 4 months. We measured circulating noradrenalin, finding it significantly elevated 2 months after HFD. To gain insights in the potential SNS modulation of immunity, we measured by microneurography SNS activation on the splenic nerve. Firing frequency (FF, spikes in 10') of splenic nerve was increased in C57Bl/6J mice on HFD (FF:432±81) as compared to LFD (FF:86±10, p<0.01). Then, we surgically removed splenic innervation by left celiac ganglionectomy (CGX) and fed mice with HFD for 4 months. Despite CGX-mice become obese similarly to sham, as shown by body weight and microCT-measured fat pad, they were protected from HTN (SBP mmHg =CGX:105±4; sham:125±5, p<0.001), suggesting that the splenic sympathetic overdrive influences BP responses but not metabolic alterations. To look for molecular determinants, we analyzed the expression of Placental Growth Factor (PlGF), previously identified as a neuroimmune mediator, and found it significantly increased in the spleen upon HFD, but only with intact SNS innervation, since CGX-mice did not increase it. In the end, PlGF KO mice subjected to HFD, although becoming obese as much as WT, were protected from HTN (SBP mmHg =PlGF KO:103±4; WT:123±6, p<0.001). Interestingly, both CGX and PlGF KO mice displayed a reduced egression of activated T cells from the spleen upon HFD feeding, suggesting that the protection observed could be related to reduced infiltration of activated lymphocytes in target organs.