Brain renin–angiotensin system: Pathophysiological mechanisms and therapeutic targets in ischemic stroke

This review aims to delineate the context-dependent, opposing actions of the angiotensin II type 1 receptor, angiotensin II type 2 receptor, and angiotensin-converting enzyme 2/ angiotensin-(1–7)/Mas receptor axis in ischemic stroke and to discuss their translational potential for neuroprotective therapy. Although recanalization cannot guarantee favorable functional outcomes for all patients with ischemic stroke, adjunctive neuroprotective targets remain limited. Dysregulation of the brain renin–angiotensin system is increasingly recognized as a potentially modifiable pathway in post-stroke brain injury. Cerebral ischemia shifts the physiological receptor balance toward angiotensin II type 1 receptor predominance, promoting vasoconstriction, blood–brain barrier disruption, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and apoptosis. Conversely, the angiotensin II type 2 receptor and Mas receptor may counter these detrimental processes through temporally distinct mechanisms. The angiotensin II type 2 receptor may provide early neuroprotection through endothelial nitric oxide synthase-mediated vasodilation, suppression of nicotinamide adenine dinucleotide phosphate oxidase, and inhibition of nuclear factor kappa-B signaling. By comparison, Mas receptor activation may facilitate delayed brain repair through mitochondrial stabilization, nuclear factor erythroid 2-related factor 2-mediated antioxidant responses, and preservation of blood–brain barrier integrity. This temporal framework, characterized by acute injury associated with angiotensin II type 1 receptor signaling, early protection associated with angiotensin II type 2 receptor signaling, and long-term recovery potentially supported by Mas receptor signaling, provides a rationale for time-sensitive therapeutic strategies. Preclinical evidence supports the neuroprotective effects of angiotensin II type 1 receptor blockers. Angiotensin II type 2 receptor agonists, such as compound 21, and glycosylated angiotensin-(1–7) peptide derivatives are promising approaches for engaging endogenous protective pathways.