Hypertension is one of most diffused chronic conditions worldwide, significantly contributing to the global disease burden. One of the major hypertension-associated organ damages is the progressive development of heart disease, also defined hypertensive heart disease (HTN-HD). This pathology often presents tracts of adaptive cardiac remodeling with preserved ejection fraction. This stage of the pathology reflects the cardiac adaptation to hemodynamic overload. Protracted and sustained overload however will often result in an aggravated condition in which the heart loses the contractile function, progressively evolving toward heart failure.
The mechanisms involved in this scenario are several and involve different systems, with a pivotal role played by the autonomic nervous system (ANS) and the immune system: the former is a well-known modulator of cardiac function and it is also capable of modulating the immune system itself; the latter is heavily involved in several aspect of hypertension and its associated organ damage and plays a role with different immune cells population in the cardiac remodeling process.
In this project we will investigate the role of the central nervous system in regulating the interplay established between ANS and immunity during HTN-HD. By using an experimental model of HTN-HD obtained by chronic infusion of Angiotensin II (AngII), we will analyze how brain regions enriched of AngII receptors, namely the circumventricular organs, can modulate the peripheral ANS to elicit the immune response from the spleen, which contribute to the process of cardiac remodeling.
Moreover, we will investigate the function that the Placental Growth Factor plays in coupling the neuro-immune interface in the spleen and thus its role in the cardiac remodeling. Achieving this goal of multilayer characterization of the pathways involved in heart failure, we will be able to identify new therapeutic targets for this pervasive and challenging chronic condition.
Hypertension is one of the most diffused chronic clinical condition worldwide and a leading risk factor or several life-threatening diseases and events. Among these, hypertensive heart disease (HTN-HD) is one of the most diffused and subtle of these conditions, further aggravating the cardiovascular disease burden of the patient and significantly lowering the quality of life of affected people. In this context becomes clear that the clinical practice and public health would largely benefit of a variety of effective therapeutic approaches particularly in patients at initial stage of disease, in which the cardiac muscle retains the ejection fraction (HFpEF).
The possibility of tackling the process of cardiac remodelling in this stage could allow treating patients to avoid the evolution toward cardiac failure stages. In the current proposal we will elucidate the role played in this process by one of the main triggers of hypertension and thus HTN-HD, the AngII. Previous literature identified a pivotal role of AngII into the brain, targeting regions in which its receptor is highly expressed as the SFO (20), while no one investigated its central effect in the context of heart failure. On the other hand, it is well known that several immune cells population interact with the myocardium playing adaptive and maladaptive roles. The investigation on the neural trigger of immune cells¿ activation will shed light on mechanisms which could be potential target of modulation for a bioelectronic or pharmacologic intervention to drive the immune processes toward reparative phenotype and to avoid the maladaptive remodelling leading to heart failure. The other major pathway analysed in this project is the angiogenic growth factor Placental Growth Factor (PlGF) whose role as neuroimmune mediator of immune activation in the spleen has been discovered by our group (21, 22). This multifaceted growth factor is capable of regulating several mechanism linking neural, immune and cardiovascular system, and thus exploring its role in cardiac remodelling would pave the way to interventions on the associated pathways to hamper the maladaptive process. Globally, our aim is to elucidate the complex interplay between the central nervous system, the immune system and the cardiovascular system in the context of HTN-HD. To accomplish this issue, we will leverage state of the art surgical, imaging, immunologic and electrophysiologic techniques to shed light on the mechanisms involved in the regulation of the single systems and their interfaces. With this total and mechanistic characterization, we will pave the way for strategies aimed at hampering the evolution of HTN-HD toward heart failure.
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