Étude du rôle de l’angiotensine II sur les fonctions cérébrales

Despite the massive prevention campaign in place, hypertension (HT) still concern one third of the world’s population and remains the first risk factor for cardiovascular diseases. HT is also an important risk factor in the development of cognitive dysfunctions from mild cognitive impairment (MCI) to vascular dementias and Alzheimer’s disease. Previous studies have identified the Renin-Angiotensin System (RAS) as the centerpiece in stroke promotion and age-associated neurodegenerative diseases. For example, recent clinical trials provided evidence that RAS inhibitors have beneficial effects on stroke risk, cognitive dysfunctions and neurodegenerative diseases, which are superiors to other anti-hypertensive drugs. Using a model of HT induced by chronic perfusion of Ang II, a peptide involved in the onset and maintenance of HT, we studied the effect of HT and Ang II on the cerebrovascular control and memory in mice. HT, now recognized as a chronic inflammatory disease, we also studied the effect of the interaction between the immune system Ang II on cerebrovascular regulation. The literature showed that HT, through the production of Ang II, increase oxidative stress, pro-inflammatory cytokines, lymphocytes and macrophages infiltration in the artery walls triggering vascular dysfunctions. Previous studies, using mesenteric arteries, demonstrated that CD4+CD25+ Foxp3+, also called T regulatory lymphocytes (Treg), reverse the vascular inflammation induced by Ang II. However, the influence of T lymphocytes on neurovascular coupling (NVC), a mechanism essential to brain homeostasis, and thus to neuronal functions had never been investigated. NVC is defined by the vascular response to a neuronal activity and depends on the collaboration between components of the neurovascular unit composed of the neurons, astrocytes, microglia and arteries. We demonstrated that Treg normalizes the cerebrovascular responses to whisker stimulations, a model of NVC, in mice chronically perfused with Ang II. Treg cells can modulate the activity of T effector cells (Th) which participate in the inflammatory response. We consequently investigated the effect of Th on vascular reactivity. Interestingly, Th alters the vascular response to whisker stimulation. Treg have the possibility to regulate the Th response through direct interaction or through the production of anti-inflammatory cytokines such as interleukin-10 or transforming growth factor (TGF)-β. Using Treg from IL-10 knock-out mice, we discovered that, without the ability to produce IL-10, the cerebrovascular response is altered in the same manner as with Th. We also found that IL-10 restores the NVC without normalizing the endothelial response in Ang II-perfused mice. These data suggest that the Treg effect depends on IL-10 production. Following these results, we searched to know whether the effect of Ang II in cerebrovascular functions correlated with a decrease in cognitive functions. We showed that a chronic perfusion of Ang II caused a spatial memory impairment. Therefore, even if the Ang II cause cerebrovascular dysfunctions shortly after perfusion, the memory impairment only shows after 3 weeks. This deficit is correlated with a decrease in synaptophysine content in the perforant pathway of the hippocampus and with an increase in β-amyloid in the cortex. The perforant pathway is connected to the entorhinal cortex which is one of the first brain region altered in Alzheimer’s disease patients. This study demonstrates that: 1) immune cells and their cytokines play a key role in the regulation of cerebral blood flow, particularly in a model of hypertension triggered by Ang II; and that Ang II alters synaptic connections, fosters the accumulation of amyloid proteins and is impairs cognitive functions. The role of inflammation in these brain defects induced by Ang II remains to be demonstrated.

Keyphrases: Lymphocyte T, Memory, T lymphocyte, Neurovascular coupling