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. We next evaluated by immunofluorescence and ELISA the levels of 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 resulted significantly protected from the BP increase 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 toward 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.

Deoxycorticosterone acetate-salt hypertension activates placental growth factor in the spleen to couple sympathetic drive and immune system activation / Perrotta, Marialuisa; Lori, Andrea; Carnevale, Lorenzo; Fardella, Stefania; Cifelli, Giuseppe; Iacobucci, Roberta; Mastroiacovo, Francesco; Iodice, Daniele; Pallante, Fabio; Storto, Marianna; Lembo, Giuseppe; Carnevale, Daniela. - In: CARDIOVASCULAR RESEARCH. - ISSN 0008-6363. - ELETTRONICO. - 114:(2018), pp. 456-467. [10.1093/cvr/cvy001]

Deoxycorticosterone acetate-salt hypertension activates placental growth factor in the spleen to couple sympathetic drive and immune system activation.

Perrotta, Marialuisa;Lembo, Giuseppe;Carnevale, Daniela
2018

Abstract

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. We next evaluated by immunofluorescence and ELISA the levels of 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 resulted significantly protected from the BP increase 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 toward 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.
2018
Deoxycorticosterone acetate (DOCA); Hypertension; Lymphocyte; Placental Growth Factor (PlGF); Sympathetic nervous system
01 Pubblicazione su rivista::01a Articolo in rivista
Deoxycorticosterone acetate-salt hypertension activates placental growth factor in the spleen to couple sympathetic drive and immune system activation / Perrotta, Marialuisa; Lori, Andrea; Carnevale, Lorenzo; Fardella, Stefania; Cifelli, Giuseppe; Iacobucci, Roberta; Mastroiacovo, Francesco; Iodice, Daniele; Pallante, Fabio; Storto, Marianna; Lembo, Giuseppe; Carnevale, Daniela. - In: CARDIOVASCULAR RESEARCH. - ISSN 0008-6363. - ELETTRONICO. - 114:(2018), pp. 456-467. [10.1093/cvr/cvy001]
File allegati a questo prodotto
File Dimensione Formato  
Perrotta_Deoxycorticosterone_2018.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 2.15 MB
Formato Adobe PDF
2.15 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1049676
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 16
  • Scopus 34
  • ???jsp.display-item.citation.isi??? 34
social impact