ACE2-Serotonin Interaction Regulates Microglial Activation and Neurovascular Function under Vascular Stress

This presentation will focus on the interplay between ACE2 and serotonin in regulating microglial states, neuroplasticity, and neurovascular function, presenting data on sex-specific cardiovascular, behavioral, and neurochemical responses under hypertensive stress in mouse models with targeted alterations of brain ACE2 signaling. Serotonin and angiotensin-converting enzyme 2 (ACE2) are key regulators of neuroplasticity and neurovascular function. Emerging evidence shows that microglial states are affected by serotonin and vascular cues, with prolonged activation leading to neuroinflammation; however, the mechanisms linking ACE2 activity, serotonin signaling, and microglial polarization remain unclear. We hypothesize that ACE2-dependent modulation of serotonin levels determines whether microglia adopt neuroprotective or neurodegenerative phenotypes, particularly under vascular stress such as hypertension. To test this, we assessed cardiovascular physiology, serotonin levels, microglial states, cell proliferation, and cognitive performance at baseline and following DOCA-salt-induced hypertension in mouse models with targeted alterations of brain ACE2 signaling, including global ACE2 knockout (ACE2-/-) and Vgat-Cre driven ACE2 deficiency in GABAergic neurons. Our data show that peripheral and central serotonin levels were generally higher in females but reduced under ACE2 deficiency. Region-specific differences were particularly evident in the hippocampus, which supports mood and memory, and in the hypothalamus, which mediates metabolic stress responses. In contrast, Vgat-Cre mice showed unchanged tryptophan but elevated serotonin levels, accompanied by increased locomotor activity and reduced anxiety-like behavior. Immunohistochemistry revealed altered cell proliferation and increased numbers of activated microglia in ACE2-/- mice. Under DOCA-salt treatment, systolic blood pressure increased in controls and female ACE2-/- mice but not in males, indicating sex-specific cardiovascular regulation; additionally, saline-infused water intake increased twofold in males and controls, but rose fivefold in female ACE2-/- mice. In behavior tests, male ACE2-/- mice exhibited increased anxiety under hypertensive conditions. Together, these findings demonstrate that ACE2 differentially regulates cardiovascular physiology and serotonin signaling with sex-specific effects on blood pressure, fluid intake, anxiety-like behavior, and hippocampal neuroplasticity. This work provides mechanistic insight into how ACE2 and serotonin interact to influence microglial function, cognition, and neurovascular health, highlighting potential avenues for interventions in hypertension-related cognitive decline and mood disorders. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.