Marialuisa Perrotta

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.

Hypertension and Dementia: Epidemiological and Experimental Evidence Revealing a Detrimental Relationship

Hypertension and dementia represent two major public health challenges worldwide, notably in the elderly population. Although these two conditions have classically been recognized as two distinct diseases, mounting epidemiological, clinical and experimental evidence suggest that hypertension and dementia are strictly intertwined. Here, we briefly report how hypertension profoundly affects brain homeostasis, both at the structural and functional level. Chronic high blood pressure modifies the cerebral vasculature, increasing the risk of Aβ clearance impairment. The latter, excluding genetic etiologies, is considered one of the main causes of Aβ deposition in the brain. Studies have shown that hypertension induces cerebral arterial stiffening and microvascular dysfunction, thus contributing to dementia pathophysiology. This review examines the existing and the updated literature which has attempted to explain and clarify the relationship between hypertension and dementia at the pathophysiological level.

Pathophysiological Links Among Hypertension and Alzheimer’s Disease

Genetic Alzheimer’s disease (AD) accounts for only few AD cases and is almost exclusively associated to increased amyloid production in the brain. Instead, the majority of patients is affected with the AD sporadic form with typical alterations of clearance mechanisms of the brain. Most studies use engineered animal models that mimic genetic AD. Since it is emerging the existence of a pathophysiological link between cardiovascular risk factors and AD etiology, the strategy to develop animal models of vascular related AD pathology could be the key toward developing novel successful therapies. On this issue, we have demonstrated that mice that have been chronically subjected to high blood pressure show deposition of amyloid aggregates, the main histological feature of AD, and loss of memory in specific tasks. More importantly, we have identified that the hypertensive challenge increases the expression of the receptor for advanced glycated end products (RAGE), leading to beta-amyloid (Aβ) deposition and learning impairment. Here, we review different murine models of hypertension, induced either pharmacologically or mechanically, leading in the long time to plaque formation in the brain parenchyma and around blood vessels. The major findings obtained till now in this particular experimental setting allow us to suggest that this appears to be a unique possibility to study the pathogenetic mechanisms of sporadic AD triggered by vascular risk factors.

The Spleen: A Hub Connecting Nervous and Immune Systems in Cardiovascular and Metabolic Diseases

Metabolic disorders have been identified as major health problems affecting a large portion of the world population. In addition, obesity and insulin resistance are principal risk factors for the development of cardiovascular diseases. Altered immune responses are common features of both hypertension and obesity and, moreover, the involvement of the nervous system in the modulation of immune system is gaining even more attention in both pathophysiological contexts. For these reasons, during the last decades, researches focused their efforts on the comprehension of the molecular mechanisms connecting immune system to cardiovascular and metabolic diseases. On the other hand, it has been reported that in these pathological conditions, central neural pathways modulate the activity of the peripheral nervous system, which is strongly involved in onset and progression of the disease. It is interesting to notice that neural reflex can also participate in the modulation of immune functions. In this scenario, the spleen becomes the crucial hub allowing the interaction of different systems differently involved in metabolic and cardiovascular diseases. Here, we summarize the major findings that dissect the role of the immune system in disorders related to metabolic and cardiovascular dysfunctions, and how this could also be influenced by neural reflexes.

Targeting Interleukin-1β Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor β Signaling

SUMMARY 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 &bgr; (TGF‐&bgr;) 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‐&bgr;. The results revealed that Smad4 inhibition activated interleukin‐1&bgr; (IL‐1&bgr;) 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‐1&bgr; antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF‐&bgr; signaling, such as those driven by SMAD4 mutations. HIGHLIGHTSSMC‐specific inducible deletion of Smad4 in adult mice provokes aortic aneurysmsThe resulting disrupted TGF‐&bgr; signaling activates IL‐1&bgr; in SMCs as a danger signalIL‐1&bgr; induces CCL2 to recruit an innate immune response harmful to the aortic wallsTargeting IL‐1&bgr; and CCL2 protects mice with disrupted TGF‐&bgr; in SMCs from aneurysms TGF‐&bgr; signaling has an unquestionable but still controversial role in the pathogenesis of aortic aneurysm. Da Ros et al. demonstrate that disruption of TGF‐&bgr; signaling in SMCs activates an autocrine IL‐1&bgr; pathway that acts as a danger signal to recruit innate immune cells in the adventitia through CCL2.

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. 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.

The Interactions of the Immune System and the Brain in Hypertension

Purpose of ReviewHypertension still represents a huge health problem, causing death and disability and rising at epidemic levels worldwide. The availability of a vast array of antihypertensive therapeutic strategies still fails to adequately treat significant fractions of refractory patients. The possible explanation to this disappointing evidence should be ascribed to the fact that myriad of mechanisms contribute to onset and maintenance of hypertension. Although we have been able to develop strategies aimed at counteracting the single mechanisms identified as master regulators of blood pressure, we still lack strategies capable to approach at the complex interactions established among the different pathophysiological mechanisms.Recent FindingsOne of the most intriguing pathophysiological interactions in hypertension emerged in the very last years is the one established between the autonomic nervous system and immunity.SummaryHere we briefly review the most important contributions revealing neural modulation of immunity in hypertension and how this novel concept is integrated in the already known multitude of regulations exerted by the autonomic nervous system in typical organs involved in blood pressure regulation.

The Multifaceted Roles of PI3Kγ in Hypertension, Vascular Biology, and Inflammation

PI3Kγ is a multifaceted protein, crucially involved in cardiovascular and immune systems. Several studies described the biological and physiological functions of this enzyme in the regulation of cardiovascular system, while others stressed its role in the modulation of immunity. Although PI3Kγ has been historically investigated for its role in leukocytes, the last decade of research also dedicated efforts to explore its functions in the cardiovascular system. In this review, we report an overview recapitulating how PI3Kγ signaling participates in the regulation of vascular functions involved in blood pressure regulation. Moreover, we also summarize the main functions of PI3Kγ in immune responses that could be potentially important in the interaction with the cardiovascular system. Considering that vascular and immune mechanisms are increasingly emerging as intertwining players in hypertension, PI3Kγ could be an intriguing pathway acting on both sides. The availability of specific inhibitors introduces a perspective of further translational research and clinical approaches that could be exploited in hypertension.