Abstract 653: Placental Growth Factor mediates Splenic Sympathetic Overdrive induced by Obesity and induces hypertension

Obesity is an epidemic condition associated with several cardiovascular comorbidities, as hypertension. Although the molecular mechanisms related to obesity-induced hypertension are not well understood, the sympathetic nervous system (SNS) overactivation typically accompanying obesity has been ascribed as one of the main culprits. Thus far, mechanistic studies focused on the effects of sympathetic overdrive on peripheral resistances. Recent data showing that SNS activation also dictates immune responses involved in hypertension, made us hypothesize whether obesity induced by high fat diet (HFD) could recruit splenic SNS efferent. Thus we subjected WT mice to HFD, as compared to low fat diet (LFD), and monitored the hypertensive response. Blood pressure (BP) started to rise after two months, and hypertensive disease became clearly manifest within 4 months. To gain mechanistic insights responsible for BP increase, we assessed peripheral SNS activation at a time point preceding overt hypertension (i.e. 2 months after HFD). We found elevated circulating noradrenalin levels in HFD mice and, more important, a specific pattern of activated splenic sympathetic overdrive, as recorded by microneurography. WT mice subjected by surgical removal of the left celiac ganglion (CGX) where the splenic nerve originate, before receiving HFD, were protected from hypertension, despite developing obesity the same. The fact that splenectomized mice showed an overlapping response to HFD, supported the conclusion that the sympathetic-immune axis is crucial for HFD-induced hypertension but not for weight regulation. To look for molecular determinants, we analyzed the expression of Placental Growth Factor (PlGF), previously identified as a neuroimmune mediator of other hypertensive challenges. PlGF was significantly overexpressed in the spleen upon HFD, but only when SNS innervation was intact, as CGX mice failed to induce its expression. In the end, PlGF KO mice subjected to HFD, although becoming obese as much as WT did, were protected from hypertension. Overall our results demonstrate that a splenic neuroimmune drive is crucial to allow the onset of hypertensive disease associated with obesity, although having no effect in body weight increase in response to HFD.