Ricerc@Sapienza

Hypertension remains a major cause of morbidity and mortality worldwide, and development of hypertensive heart disease (HTN-HD) is an important contributor. HTN-HD develops secondary to left ventricle (LV) pressure overload and neurohormonal hyperactivation. Chronic HTN can lead to the development of HF with a preserved ejection fraction (HFpEF) - which accounts for 50% of HF admission, yet has no approved therapies. HFpEF reflects initially adaptive remodeling aimed at normalizing wall stress during HTN, but progresses to increased LV stiffness and filling pressures and, if chronic, depressed LV function [HF with reduced EF (HFrEF)]. Mechanisms that lead to HTN-HD involve numerous pathways and are typically intertwined with unbalance of autonomic nervous system (ANS) regulation.
The spleen, a primary immune organ, is an important and underappreciated target of ANS during HTN-HD progression. We previously found in the Angiotensin II model of hypertension, ANS activates a previously unknown sympathetic efferent modulating immune responses: the splenic sympathetic nerve activity (SSNA). We also found that the activation of SSNA during hypertension is dependent on a preganglionic parasympathetic pathway passing through the celiac efferent branch of the vagus nerve (CVN). Interestingly, vagus nerve functions are also modulated by hemodynamic challenges imposed by hypertension on the LV. Whether and how the two functions (immune modulating and hemodynamic) of the vagus nerve are related to each other is still unknow. We have preliminary data showing that not only AngII but also a direct mechanic hemodynamic challenge imposed on the LV by ligation of the transverse aortic arch (TAC model) activates the SSNA.
This project will focus on dissecting how the neuroimmune vagus-splenic connection is recruited by hemodynamic overload during the different phases of HTN-HD and how this ANS pathway affects immune responses involved in adaptive versus maladaptive cardiac remodeling.