Abstract 020: PLGF VEGFB Neuropilin1 a Neuroimmune Mechanism Necessary for the Initiation of the Adaptive Immune Response Recruited by Angiotensin II to Induce Hypertension and Target Organ Damage

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Vascular endothelial growth factors (VEGFs) are mainly known as angiogenic factors but they also play less explored immune-modulating functions. In the past years we found that one of the VEGF family members, Placental Growth Factor (PlGF), is critical for hypertension. PlGF is recruited in the spleen by Angiotensin II (AngII) to prime T cell costimulation through the expression of CD86 in antigen presenting cells (APCs). Here we show that AngII also recruits VEGF-B, PlGF homolog, in the spleen and its selective splenic ablation, obtained by transplanting VEGF-B KO spleen in WT mice, protects from immune activation and hypertension. In the search for a downstream common mediator of PlGF/VEGF-B, we analyzed the splenic expression of VEGFR1, a major candidate receptor, which was activated by AngII. However, mice genetically defective of VEGFR1 signaling (Flt1-TK) become hypertensive as WT when subjected to AngII (SBP: Flt1-TK 139±2; WT 138±2; ***p< 0.001), thus ruling out its role. Since the expression of PlGF/VEGF-B was confined to the stromal and marginal zone (MZ), where lymphoid and innate zones are entangled with noradrenergic fibers, we analyzed Neuropilin1 (Nrp1), a secondary receptor for PlGF/VEGF-B, functioning in neuronal guidance and dendritic cell maturation. Immunofluorescence revealed that AngII increases Nrp1 expression and flow cytometry indicated a localization of the receptor on myeloid APCs. Splenic denervation reduced Nrp1 expression on APCs (from 29 ± 3% to 14 ± 2%), further supporting that it mediates PlGF/VEGF-B signaling. In the end, we selectively deleted the receptor in myeloid lineage, generating Nrp1 myeloidKO mice, thus blocking the effect of PlGF/VEGF-B on the APCs. The in vitro induction of DC maturation in monocytes isolated from Nrp1 myeloidKO mice failed to produce mature APC, thus indicating the requirement of this pathway for the initiation of the adaptive immune response. AngII fails to induce T cell costimulation and egression from the spleen, and ultimately increase BP (SBP: Nrp1 myeloidWT mice 140±3; Nrp1 myeloidKO mice 105±2; ***p< 0.001). Overall we demonstrate that PlGF/VEGF-B/Nrp1 is a critical neuroimmune mechanism responsible for initiation of the adaptive immune response in hypertension.