Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Abstract

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.

G-Protein-Coupled Estrogen Receptor Expression in Rat Uterine Artery Is Increased by Pregnancy and Induces Dilation in a Ca2+ and ERK1/2 Dependent Manner

“…The following supporting information can be downloaded at: . References [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ] are cited in Supplementary Materials.…”

Role of estrogen in treatment of female depression

“…The research of Saleh Zahedi Asl proved that both ERα and ERβ agonists can inhibit BBB leakage, and ERα agonists may play a more important role [ 80 ]. Vascular pericyte migration is a hallmark of BBB disruption following injury, infection, and inflammation, and TNF-α-induced migration of human brain vascular pericytes was blocked by E2, while ERα and ERβ agonists were found to have similar effects [ 82 ].…”

Uso de contraceptivos orais contendo estrogênio associado ao risco de desenvolvimento do AVE isquêmico

“…As evidências de que o risco maior de acidente vascular encefálico é após a menopausa levantam a hipótese de que o estrogênio pode ser neuroprotetor. Esse hormônio auxilia na regulação de mudanças dinâmicas da estrutura e da função vascular, protegendo contra o remodelamento vascular associado à doença arterial coronariana e à lesão endotelial, além de prevenir a neuroinflamação descontrolada (Kurmann et al, 2021).…”

“…O acidente vascular encefálico (AVE) é a terceira causa de mortalidade em mulheres e mata duas vezes mais mulheres do que o câncer de mama (Kurmann et al, 2021). O AVE é uma das principais causas de incapacidades e mortes entre as mulheres em todo o mundo.…”