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Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis
Lisa Kurmann1, Michal Okoniewski2, Raghvendra K Dubey1,3
1Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland.
Cells
|September 28, 2021
Summary
Estradiol, a form of estrogen, protects the blood-brain barrier (BBB) by regulating pericyte activity. This finding offers new insights into stroke prevention and treatment strategies for women.
Area of Science:
- Neuroscience
- Endocrinology
- Vascular Biology
Background:
- Stroke is a leading cause of mortality in women, with blood-brain barrier (BBB) disruption playing a key role in its pathophysiology.
- Estrogen's protective vascular effects are known, but its specific impact on BBB integrity and stroke remains unclear.
- Pericytes are crucial for BBB integrity, and their regulation by estradiol is hypothesized to influence BBB function.
Purpose of the Study:
- To investigate the impact of estradiol on human brain vascular pericyte (HBVP) functions relevant to BBB integrity.
- To determine the specific estrogen receptors (ERs) involved in estradiol's effects on pericytes.
- To elucidate the intracellular mechanisms mediating estradiol's influence on pericyte migration and BBB function.
Main Methods:
- HBVPs were treated with estradiol, and cell migration and proliferation were assessed.
- The effects of estradiol on tumor necrosis factor-alpha (TNFα)-induced pericyte migration were evaluated using specific ER agonists and antagonists.
- Intracellular signaling pathways (AKT and MAPK) were analyzed, and transendothelial electrical resistance (TEER) was measured to assess BBB function.
Main Results:
- Estradiol inhibited basal and TNFα-induced pericyte migration, an effect mediated by ER-α and ER-β.
- Estradiol reduced TNFα-induced MAPK phosphorylation, which was critical for abrogating migratory actions.
- Estradiol enhanced BBB barrier function in co-cultures of pericytes and endothelial cells and modulated gene expression related to cell migration.
Conclusions:
- Estradiol modulates pericyte activity, specifically inhibiting migration via ER-α and ER-β signaling pathways.
- These modulatory effects contribute to improved endothelial barrier integrity, suggesting a protective role against BBB disruption.
- Findings provide the first evidence of estradiol's direct impact on pericyte function, offering potential therapeutic targets for stroke.
