Introduction and Hypothesis:
In the past several years, there has been mounting interest in the roles played by immunity in hypertension. However, where and how the immune system gets activated under hypertensive stimuli to contribute to hypertension, is still enigmatic. The activation of effector T cells in hypertension suggests that antigen presentation by a specialized subset of innate cells represents an important component that participates in this process. In particular, it has been recently shown that T cell costimulation by B7 ligands is an important mechanism in the development of hypertension.
Methods and Results:
Here we demonstrate a novel splenic mechanism driven by Placental Growth Factor (PlGF) and regulating T cells costimulation in AngII-induced hypertension. We have found that PlGF is necessary to allow CD86 expression, crucial in AngII hypertension. Moreover, we show that this effect is exerted by a Sirt1-dependent epigenetic modulation of Timp3 expression in splenic macrophages, obtained by controlling p53 repressor activity on its promoter. Since the brain plays a pivotal role in AngII-induced hypertension and it is known that a selective removal of sympathetic innervation to the splanchnic district, obtained by celiac ganglionectomy (CGX), markedly attenuated hypertension, we looked whether the early induction of splenic PlGF upon AngII could be mediated by a nervous drive. Indeed, when we performed CGX in WT mice, splenic PlGF was markedly reduced, thus demonstrating that is is activated by Ang-II induced SNS overactivity. Importantly, we show that this neuroimmune mechanism driven by PlGF is crucial for the onset of hypertension, since PlGF KO mice display a clear-cut protection from the typical AngII-hypertensive response and from T cells infiltration in vessels and kidneys. Finally, chimeric mice generated by spleen transplantation (PlGF KO spleen in WT background and vice versa), allowed us to finally demonstrate that PlGF is indispensable in the spleen for the onset of hypertension.
Conclusions:
Summarizing, our study brought to light both how important the neuroimmune drive in the spleen is in the genesis of hypertension and, at same time, unveil that PlGF is the molecular pathway recruited in the spleen to control BP raising.
Celiac Ganglionectomy Attenuates Central Sodium‐Induced Hypertension
