TY - JOUR
T1 - Deoxycorticosterone acetate-salt hypertension activates placental growth factor in the spleen to couple sympathetic drive and immune system activation
AU - Perrotta, Marialuisa
AU - Lori, Andrea
AU - Carnevale, Lorenzo
AU - Fardella, Stefania
AU - Cifelli, Giuseppe
AU - Iacobucci, Roberta
AU - Mastroiacovo, Francesco
AU - Iodice, Daniele
AU - Pallante, Fabio
AU - Storto, Marianna
AU - Lembo, Giuseppe
AU - Carnevale, Daniela
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Aims Chronic increase of mineralocorticoids obtained by administration of deoxycorticosterone acetate (DOCA) results in salt-dependent hypertension in animals. Despite the lack of a generalized sympathoexcitation, DOCA-salt hypertension has been also associated to overdrive of peripheral nervous system in organs typically targeted by blood pressure (BP), as kidneys and vasculature. Aim of this study was to explore whether DOCA-salt recruits immune system by overactivating sympathetic nervous system in lymphoid organs and whether this is relevant for hypertension. Methods and results To evaluate the role of the neurosplenic sympathetic drive in DOCA-salt hypertension, we challenged splenectomized mice or mice with left coeliac ganglionectomy with DOCA-salt, observing that they were both unable to increase BP. Then, we evaluated by immunofluorescence and ELISA levels of the placental growth factor (PlGF) upon DOCA-salt challenge, which significantly increased the growth factor expression, but only in the presence of an intact neurosplenic sympathetic drive. When PlGF KO mice were subjected to DOCA-salt, they were significantly protected from the increased BP observed in WT mice under same experimental conditions. In addition, absence of PlGF hampered DOCA-salt mediated T cells co-stimulation and their consequent deployment towards kidneys where they infiltrated tissue and provoked end-organ damage. Conclusion Overall, our study demonstrates that DOCA-salt requires an intact sympathetic drive to the spleen for priming of immunity and consequent BP increase. The coupling of nervous system and immune cells activation in the splenic marginal zone is established through a sympathetic-mediated PlGF release, suggesting that this pathway could be a valid therapeutic target for hypertension.
AB - Aims Chronic increase of mineralocorticoids obtained by administration of deoxycorticosterone acetate (DOCA) results in salt-dependent hypertension in animals. Despite the lack of a generalized sympathoexcitation, DOCA-salt hypertension has been also associated to overdrive of peripheral nervous system in organs typically targeted by blood pressure (BP), as kidneys and vasculature. Aim of this study was to explore whether DOCA-salt recruits immune system by overactivating sympathetic nervous system in lymphoid organs and whether this is relevant for hypertension. Methods and results To evaluate the role of the neurosplenic sympathetic drive in DOCA-salt hypertension, we challenged splenectomized mice or mice with left coeliac ganglionectomy with DOCA-salt, observing that they were both unable to increase BP. Then, we evaluated by immunofluorescence and ELISA levels of the placental growth factor (PlGF) upon DOCA-salt challenge, which significantly increased the growth factor expression, but only in the presence of an intact neurosplenic sympathetic drive. When PlGF KO mice were subjected to DOCA-salt, they were significantly protected from the increased BP observed in WT mice under same experimental conditions. In addition, absence of PlGF hampered DOCA-salt mediated T cells co-stimulation and their consequent deployment towards kidneys where they infiltrated tissue and provoked end-organ damage. Conclusion Overall, our study demonstrates that DOCA-salt requires an intact sympathetic drive to the spleen for priming of immunity and consequent BP increase. The coupling of nervous system and immune cells activation in the splenic marginal zone is established through a sympathetic-mediated PlGF release, suggesting that this pathway could be a valid therapeutic target for hypertension.
KW - Deoxycorticosterone acetate
KW - Hypertension
KW - Lymphocyte
KW - Placental growth factor
KW - Sympathetic nervous system
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U2 - 10.1093/cvr/cvy001
DO - 10.1093/cvr/cvy001
M3 - Article
AN - SCOPUS:85042927689
VL - 114
SP - 456
EP - 467
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 3
ER -