ACE2’s main function is to regulate arterial blood pressure (BP) by changing total peripheral resistance to blood flow and fluid balance [
14,
23,
78]. This is part of the well-known renin-angiotensin system (RAS) (Fig.
2). While the components of RAS pathways are present in the brain and the periphery, they do not directly interact, but cooperate via centers in the brain to maintain blood pressure and plasma volume [
14]. RAS components are widely expressed in the brain, especially in regions that regulate the cardiovascular system (CVS) and osmoregulation, including the hypothalamic paraventricular nuclei, supraoptic nuclei, ventrolateral medulla and the solitary nucleus [
79]. Angiotensin-11, generated via ACE, increases BP by increasing vasoconstriction of arterioles and fluid retention by increasing the secretion of aldosterone, in addition to inflammation, oxidative stress and injury. Degradation of angiotensin-1 and angiotensin-11 by ACE2 generates angiotensin (1–7) and angiotensin (1–9), which reduce BP, by increasing vasodilation and reducing plasma volume, inflammation, oxidative stress and injury [
80]. For example, the phenotype of ACE2
−/− mice includes hypertension, behavioural dysfunction, impaired serotonin synthesis and neurogenesis [
81]. In addition, ACE2 polymorphism is associated with essential hypertension [
82]. Increased levels of brain ACE2 are associated with delay in cognitive decline [
83]. Thus, ACE and ACE2 have a synergistic effect (Fig.
2). Inactivation of ACE2 as seen with SARS-CoV-2 infection could exacerbate angiotensin-11 adverse effects, such as inflammation, and perhaps, contribute to COVID-19 adverse effects. Reduced ACE2 levels are associated with sperm-related infertility [
84], pulmonary hypertension [
85], kidney disease [
86] and acute lung injury [
87,
88]. In contrast, estrogen is reported to increase ACE2 activity [
89], and protects against CVD. Thus, ACE2 has a wide range of beneficial effects, but is not directly associated with initiation of inflammation.