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 (AT₁) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT₁ 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 AT₁ 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 AT₁ signaling and the development of biased AT₁ 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 AT₁ activation. In this paper, we review the involvement of AT₁ 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 AT₁ agonists could be considered as new therapeutic avenues for cerebrovascular diseases.