A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication

The crucial role of the immune system in hypertension is now widely recognized. We previously reported that hypertensive challenges couple the nervous drive with immune system activation, but the physiological and molecular mechanisms of this connection are unknown. Here, we show that hypertensive challenges activate splenic sympathetic nerve discharge to prime immune response. More specifically, a vagus-splenic nerve drive, mediated by nicotinic cholinergic receptors, links the brain and spleen. The sympathetic discharge induced by hypertensive stimuli was absent in both coeliac vagotomized mice and in mice lacking α7nAChR, a receptor typically expressed by peripheral ganglionic neurons. This cholinergic-sympathetic pathway is necessary for T cell activation and egression on hypertensive challenges. In addition, we show that selectively thermoablating the splenic nerve prevents T cell egression and protects against hypertension. This novel experimental procedure for selective splenic denervation suggests new clinical strategies for resistant hypertension

Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling

Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations

Contrasting styles of (U)HP rock exhumation along the Cenozoic Adria-Europe plate boundary (Western Alps, Calabria, Corsica)

Since the first discovery of ultrahigh pressure (UHP) rocks 30 years ago in the Western Alps, the mechanisms for exhumation of (U)HP terranes worldwide are still debated. In the western Mediterranean, the presently accepted model of synconvergent exhumation (e.g., the channel-flow model) is in conflict with parts of the geologic record. We synthesize regional geologic data and present alternative exhumation mechanisms that consider the role of divergence within subduction zones. These mechanisms, i.e., (i) the motion of the upper plate away from the trench and (ii) the rollback of the lower plate, are discussed in detail with particular reference to the Cenozoic Adria-Europe plate boundary, and along three different transects (Western Alps, Calabria-Sardinia, and Corsica-Northern Apennines). In the Western Alps, (U)HP rocks were exhumed from the greatest depth at the rear of the accretionary wedge during motion of the upper plate away from the trench. Exhumation was extremely fast, and associated with very low geothermal gradients. In Calabria, HP rocks were exhumed from shallower depths and at lower rates during rollback of the Adriatic plate, with repeated exhumation pulses progressively younging toward the foreland. Both mechanisms were active to create boundary divergence along the Corsica-Northern Apennines transect, where European southeastward subduction was progressively replaced along strike by Adriatic northwestward subduction. The tectonic scenario depicted for the Western Alps trench during Eocene exhumation of (U)HP rocks correlates well with present-day eastern Papua New Guinea, which is presented as a modern analog of the Paleogene Adria-Europe plate boundary

Nuove strategie di riparazione cardiaca dell’infarto del miocardio tramite l’utilizzo di cellule iperesprimenti il fattore di trascrizione OTX2

La rigenerazione cardiaca dopo infarto del miocardio è un argomento ancora molto dibattuto e poco chiarito. In questo scenario, il presente lavoro di tesi fornisce un nuovo approccio sperimentale basato su iniezione ecoguidata, in cuori di topo, di cellule iperesprimenti il fattore di crescita Otx2, dopo tre giorni dalla induzione dell’infarto per occlusione permanente dell’arteria coronaria ascendente anteriore. I cuori di topi con infarto, con infarto e iniettati con cellule WT di controllo e con infarto e iniettati con cellule iperesprimenti OTX2 sono stati seguiti per mezzo di ecocardiografia, usando come metodo di calcolo dei parametri funzionali le formule di Simpson e l’analisi dello strain del tessuto cardiaco. La somministrazione delle cellule OTX2 si è dimostrata efficace nel proteggere i cuori dalla progressione del danno funzionale che avviene dopo l’infarto cardiaco. L’analisi istologica dei cuori iniettati, non ha mostrato la presenza delle cellule iperesprimenti OTX2 integrate nel tessuto cardiaco e quindi si è supposto un effetto paracrino. La ricerca, ancora in corso, dei fattori espressi dalle cellule OTX2 e che possano essere associati al miglioramento della funzione cardiaca ha dimostrato che queste cellule producono alcuni di questi fattori già descritti in letteratura. Questo lavoro propone un metodo di indagine innovativo per la ricerca di terapie rigenerative del tessuto cardiaco infartuato e focalizza l’attenzione su fattori paracrini che possano dare un contributo alla rigenerazione cardiaca

Placental Growth Factor Regulates Cardiac Inflammation Through the Tissue Inhibitor of Metalloproteinases-3/Tumor Necrosis Factor-alpha-Converting Enzyme Axis Crucial Role for Adaptive Cardiac Remodeling During Cardiac Pressure Overload

Background-Heart failure is one of the leading causes of mortality and is primarily the final stage of several overload cardiomyopathies, preceded by an early adaptive hypertrophic response and characterized by coordinated cardiomyocyte growth, angiogenesis, and inflammation. Therefore, growth factors and cytokines have to be critically regulated during cardiac response to transverse aortic constriction. Interestingly, the dual properties of placental growth factor as an angiogenic factor and cytokine make it a candidate to participate in cardiac remodeling in response to hemodynamic overload. Methods and Results-After transverse aortic constriction, placental growth factor knockout mice displayed a dysregulation of cardiac remodeling, negatively affecting muscle growth. Molecular insights underscored that this effect was ascribable mainly to a failure in the establishment of adequate inflammatory response owing to an impaired activity of tumor necrosis factor-alpha-converting enzyme. Interestingly, after transverse aortic constriction, placental growth factor knockout mice had strongly increased levels of tissue inhibitor of metalloproteinases-3, the main natural TACE inhibitor, thus indicating an unbalance of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-alpha-converting enzyme axis. Strikingly, when we used an in vivo RNA interference approach to reduce tissue inhibitor of metalloproteinases-3 levels in placental growth factor knockout mice during transverse aortic constriction, we obtained a complete phenotype rescue of early dilated cardiomyopathy. Conclusions-Our results demonstrate that placental growth factor finely tunes a balanced regulation of the tissue inhibitor of metalloproteinases-3/tumor necrosis factor-alpha-converting enzyme axis and the consequent TNF-alpha activation in response to transverse aortic constriction, thus allowing the establishment of an inflammatory response necessary for adaptive cardiac remodeling. (Circulation. 2011;124:1337-1350.

PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice

Cardiovascular diseases, including cardiomyopathy, are the major complications in diabetes. A deeper understanding of the molecular mechanisms leading to cardiomyopathy is critical for developing novel therapies. We proposed phosphoinositide3-kinase gamma (PI3Kγ) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kγ in cardiac remodeling to pressure overload. Given the availability of a pharmacological inhibitor of this molecular target GE21, we tested the validity of our hypothesis by inducing diabetes in mice with genetic ablation of PI3Kγ or knock-in for a catalytically inactive PI3Kγ

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

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.

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.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