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

• Main Authors: Céline Delaitre, Michel Boisbrun, Sandra Lecat, François Dupuis
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: International Journal of Molecular Sciences
• Subjects: AT₁ receptor; Angiotensin II; cerebrovascular disease; biased agonism; beta-arrestin; RAS
• Online Access: https://www.mdpi.com/1422-0067/22/13/6738

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.