Impact of the renin–angiotensin system on the endothelium in vascular dementia: Unresolved issues and future perspectives

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.