Abstract 454: Plgf Mediates A Neuroimmune Interaction In The Spleen To Allow The Onset Of Hypertension
In the past several years, there has been mounting interest in the roles played by immunity in hypertension, an health problem affecting over 1 billion people worldwide. 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, is still enigmatic.
Here we found an unprecedented splenic neuroimmune pathway driven by Placental Growth Factor (PlGF) during hypertension. The hypertensive response induced by chronic AngII infusion (28days) was completely prevented in PlGF KO mice (WT AngII 140±2 vs PlGF KO AngII 103±3 mmHg), as well as the typical end organ damage and immune cells infiltration. To determine whether the involvement of PlGF had a causal role or was merely a consequence of the failure in BP raise, we analyzed vessels and kidney early after AngII infusion (3days), before BP increase (WT AngII 108±3 vs PlGF KO AngII 105±1), finding that PlGF absence already protected from T cells infiltration. We also uncover that the splenic PlGF is essential for hypertension, through a noradrenergic drive mediated by the celiac ganglion. An intact neuroimmune interaction of the celiac ganglion on the spleen was needed to have PlGF release upon AngII and chimeric mice, generated by spleen transplantation, demonstrated that the ablation of PlGF in the spleen (KO spleen into WT mice) was sufficient to protect from hypertension. At the molecular level, we found that PlGF released in the spleen exerted a repression of the tissue protein of inflammation Timp3 through p53. In particular, while in WT splenocytes the Timp3 transcriptional repressor region was bound by its molecular repressor p53 upon AngII, PlGF KO splenocytes showed the Timp3 repressor region free from p53, as evidenced by ChIP. Finally, we demonstrated that this pathway is necessary to control T cells costimulation, through the regulation of CD86 expression, and allow their deployment toward classical organs involved in hypertension. Overall, we demonstrate that PlGF mediates the neuroimmune interaction in the spleen, organizing a unique and non redundant response that allows and is necessary for the onset of hypertension.
Author Disclosures: D. Carnevale: None. F. Pallante: None. V. Fardella: None. M. De Lucia: None. S. Fardella: None. R. Iacobucci: None. G. Lembo: None.
- © 2014 by American Heart Association, Inc.