Although several therapeutical strategies have been developed against the main components involved in the regulation of blood pressure (BP), an optimum control in some hypertensive patients is still flawed, suggesting that mechanisms still unidentified, sustain the increase of BP. Interestingly, an emerging area of investigation revealed that adaptive immunity is a central player of hypertension, since mice devoid of T lymphocytes were protected from AngII-induced hypertension. However, how hypertensive stimuli, like AngII, can afford this, still represents a fascinating enigma, challenging the search for molecular players, capable to bridge vascular responses to immune cells and probably orchestrating the still unveiled role of immune system in hypertension.
Here we demonstrate an unprecedented splenic immune pathway driven by Placental Growth Factor (PlGF), an “angiogenic cytokine” acting as a bridge between the cardiovascular and immune system during onset of hypertension. We found that the typical hypertensive response induced by chronic AngII infusion, was completely prevented in mice with genetic deletion of PlGF, as well as the typical end organ damage induced by hypertension and immune cells infiltration in target organs. To determine whether the involvement of PlGF in immune system activation and T cells infiltration during AngII-induced hypertension had a causal role or was merely a consequence of the failure in BP raise, we analyzed both vessels and kidney, early after AngII infusion, i.e. before BP increase. Strikingly, PlGF absence protected from early infiltration of both CD4+ and CD8+ T cells. More interesting, we unveil that the spleen is indispensable in the genesis of hypertension by releasing PlGF, that orchestrates the T cell response, necessary for blood pressure raising. In particular, we show that splenic PlGF acts as a negative checkpoint of a tissue protein of inflammation (Timp3), a repressor of T cell costimulation axis, thus allowing T cell activation and egression from spleen. Basically, this breakthrough in a key immune pathway determining blood pressure elevation, holds a great translational promise for patients with refractory disease and multiple complications.