Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis
| Autor: | Raghvendra K. Dubey, Lisa Kurmann, Michal J. Okoniewski |
|---|---|
| Přispěvatelé: | University of Zurich, Dubey, Raghvendra K |
| Rok vydání: | 2021 |
| Předmět: |
QH301-705.5
medicine.drug_class Estrogen receptor 610 Medicine & health 2700 General Medicine blood–brain barrier Blood–brain barrier Article Cell Movement TNFα medicine Humans Biology (General) Phosphorylation Protein kinase B Cells Cultured Cell Proliferation Inflammation Estradiol Tumor Necrosis Factor-alpha Chemistry Gene Expression Profiling Brain Endothelial Cells COVID-19 PHTPP Cell migration General Medicine 10175 Clinic for Reproductive Endocrinology blood-brain barrier estrogen receptor MAPK stroke Cell biology medicine.anatomical_structure Gene Expression Regulation Receptors Estrogen Estrogen Pericyte Mitogen-Activated Protein Kinases Pericytes Proto-Oncogene Proteins c-akt GPER |
| Zdroj: | Cells, 10 (9) Cells Volume 10 Issue 9 Cells, Vol 10, Iss 2314, p 2314 (2021) |
| ISSN: | 2073-4409 |
| DOI: | 10.3390/cells10092314 |
| Popis: | Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity. Cells, 10 (9) ISSN:2073-4409 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|