Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT(1)) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT(1) receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT(1) in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT(1) signaling and the development of biased AT(1) agonists, able to selectively activate the β-arrestin transduction pathway rather than the G(q) pathway, have led to new therapeutic strategies to target detrimental effects of AT(1) activation. In this paper, we review the involvement of AT(1) in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT(1) agonists could be considered as new therapeutic avenues for cerebrovascular diseases.