Grant: Operating Grant

Angiotensin II exerts detrimental effects on cerebral circulation, but the underlying mechanisms remains to be elucidated. In particular, Angiotensin II impairs the increase in cerebral blood flow produced by neural activity (neurovascular coupling), a critical mechanism that matches substrate delivery with energy demands in brain. Because impaired neurovascular coupling increases the vulnerability of the brain, it is important to understand how changes in vascular tone in response to neural activity may be altered. Our preliminary data showed that Angiotensin II exerts powerful proinflammatory effects in brain cells including astrocytes. Astrocytes play a pivotal role in neurovascular coupling by transducing neural activity into a Ca2+ increase that modulates cerebrovascular tone. However, in some brain pathologies, astrocytes may become reactive, a process also called astrogliosis and characterized by inflammatory responses and alterations of Ca2+ signalling. Accordingly, the major objective of this research program is to study the role of inflammation in the effect of Angiotensine II on neurovascular coupling. In particular, we will investigate the effect of different components of the immune system on neurovascular coupling and astrocyte molecular signaling. These studies will be conducted in brain slices as well as in living mice coupled to state-of-the-art microscopy techniques. Thus these studies will improve our understanding of Angiotensin II induced neurovascular coupling impairment, and may provide further therapeutic target to reduce premature disability and death from dysfunctional cerebral blood flow.