Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response

Abstract

Physical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1-7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1-7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism.

ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models

“…However, when we replaced serotonin in the brain by oral administration of glycyl-l-tryptophan running-induced neurogenesis was not rescued. Since we also present evidence that Ang II and Ang-(1-7) are not involved in this effect, the downstream mediator of ACE2 in the regulation of neurogenesis remains elusive [85].…”

“…**p < 0.01, ***p < 0.001 versus WT. Reproduced with permission from [85] which ACE2 may influence brain function. Therefore, future therapeutic applications should be carefully evaluated for possible unwanted effects mediated by other hormone systems than the RAS.…”

“…Serotonin is a monoamine that acts as an autacoid in the periphery and as a neurotransmitter in the brain. Since tryptophan is the precursor of serotonin synthesis, the impaired tryptophan uptake resulted in decreased serotonin synthesis and reduced levels in blood and brain [85] (Fig. 2).…”

“…Besides other numerous functions in the central nervous system, serotonin is essential for exercise-induced hippocampal neurogenesis [86]. Therefore, we analyzed ACE2-deficient mice for this phenotype and discovered that exercise-induced cell proliferation in the dentate gyrus is abolished in these animals [85]. However, when we replaced serotonin in the brain by oral administration of glycyl-l-tryptophan running-induced neurogenesis was not rescued.…”

COVID-19 and intracerebral haemorrhage: causative or coincidental?

“…Angiotensin II receptors are also expressed in circumventricular organs and in cerebrovascular endothelial cells, which play a role in the regulation of multiple functions in the brain, including regulation of hormone formation and sympathoadrenal system, water and sodium intake, vascular autoregulation and cerebral blood flow [5]. Angiotensin II is a vasoconstrictor which has a proinflammatory effect [6]. Thus, it is reasonable to hypothesize that brain ACE II could be involved in COVID-19 infection and its dysfunction, leading to disruption of autoregulation as well as blood pressure spikes due to arterial wall rupture.…”