ACE2 receptor and angiotensin (1–7) (ANG (1–7))
The second factor that plays a role in the neurological manifestations of SARV-CoV-2 is the ACE2 receptor. ACE2 is a carboxypeptidase that converts angiotensin II into ANG (1–7), which is an essential component of the renin–angiotensin system.35 One of the main sites that ANG (1–7) is synthesized and has a downstream effect on is endothelial cells;36 it stimulates the release of prostaglandin and nitric oxide,37,38 enhances the metabolic actions of bradykinin, and inhibits smooth muscle cell growth.39 Additionally, ANG (1–7) enhances the vagal.40,41 It also induces a decrease in tyrosine hydroxylase expression, the rate-limiting enzyme in catecholamine biosynthesis, decreasing brain catecholaminergic activity; ANG (1–7) is neuroprotective.42 In recent rat models, central administration of ANG-(1–7) reduced neurological deficits and infarct size in ischemic stroke.43,44 Virus-mediated downregulation of ACE2 has been suggested to underlie the pathology of severe acute respiratory syndrome coronavirus infection.45,46 Therefore, binding of SARS-CoV-2 to the ACE2 receptor may similarly inhibit its downstream effect via pathway downregulation or cell lysis, ultimately decreasing ANG (1–7) synthesis. This may counteract its neuroprotective properties and blood pressure autoregulation (increase in sympathetic activity).