Stress is a significant risk factor for essential hypertension and an important modulator of the sympathetic nervous system (SNS). Only in the last years of researches in this field, it was demonstrated that a chronic exposure to social stress directly affects the adaptive immunity by enhancing the peripheral SNS. In our preliminary data, we observed that mice lacking angiotensin 1a receptor (AT1aR) in the paraventricular nucleus of hypothalamus (PVN), obtained by crossing Sim1Cre mice with AT1aRflox mice, are protected from blood pressure increase after chronic angiotensin II (AngII) infusion, indicating that this brain region is important in mediating blood pressure responses. Furthermore, we also observed that the activity of the splenic sympathetic nerve (SSNA) in these mice is reduced as compared to wild type mice after chronic exposure to AngII. More interesting, the PVN is a crucial station mediating stress responses through the activation of the hypothalamic-pituitary¿adrenal axis (HPA).
First, to evaluate the efficacy of the gene deletion, we will realize an ex vivo laser microdissection of PVN and genomic PCR of AT1aR in AT1aRflox-Sim1-Cre+ mice and their control AT1aRflox-Sim1-Cre-. Then, we will subject AT1aRflox-Sim1-Cre mice, and AT1aRwt-Sim1-Cre- mice as controls, to a protocol of chronic stress for 3 weeks and we will measure arterial blood pressure by plethysmography, SSNA by microneurography and splenic immunity by immunohistochemistry. The aim of this project is to explore whether AT1aRs in PVN are important to drive sympathetic outflow and to modulate the activation of splenic immunity, allowing to identify a brain center controlling a specific efferent pathway in stress-induced hypertension.
The realization of our study could provide substantial insights in hypertension since they highlight a completely novel sympathetic pathway activated by a stress stimulus and the possibility to control its activity at a central level. Stress is an important factor in the pathogenesis of human hypertension and this relationship has been suggested to be in part caused by an increased sympathetic activity (Esler et al., 2008). We previously examined in depth the role of splenic sympathetic nerve activity (SSNA) in directing immune cells mobilization upon chronic hypertensive challenges (Carnevale et al., 2014, 2016). The integrity of this nerve is necessary to prime immune responses in hypertension and consequently to promote functional and structural damages in peripheral organs (Carnevale et al., 2016; Perrotta et al., 2018a, 2018b). Given our previous observation of an increased SSNA in two different murine models of hypertension, induced by Angiotensin II or DOCA-salt, here we asked whether a chronic stimulus, like the stress, can induce a common autonomic response.
In the present project, our hypothesis is that a particular brain nucleus, the paraventricular nucleus of the hypothalamus (PVN) senses a peripheral hypertensive challenge, as chronic stress, and in turn activates the splenic sympathetic nervous pathway. Further understanding of the role of psychological stress in controlling blood pressure and the associated immune response, could provide the potential for the development of new treatment strategies for hypertension. Despite the basic research implications in this field what is more important is the opportunity in terms of applications and therapeutic potential with the aim to develop novel therapeutic strategies for hypertension with two specific potential markers. At the central level, we will candidate the PVN as a brain nucleus able to direct the activity of the splenic nerve, and, at the periphery, we will target the SNS in a specific district, where it modulates adaptive immune system.
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