Patient Sera from the First Week Postpartum after Preeclampsia Increase Human Blood Brain Barrier Permeability
Noora Haghighi1, Ugur Akcan2, Mary Claire Tuohy2, Whitney Booker2, Natalie Bello3, Dritan Agalliu2, Eliza Miller1
1Neurology, Columbia University, 2Columbia University, 3Cedars-Sinai Medical Center
Objective:
Determine the effects of patient sera obtained in the first week postpartum after preeclampsia on human blood-brain barrier (BBB) function.
Background:
Preeclampsia, a hypertensive disorder of pregnancy associated with endothelial dysfunction, carries high risk for postpartum neurovascular complications. Animal studies suggest maternal BBB dysfunction in preeclampsia.
Design/Methods:
We recruited preeclamptic and normotensive pregnant women and collected serum within 7 days postpartum. We developed a 3D human BBB model in the MIMETAS 3D platform with flow that incorporates brain microvascular endothelial cells (20,000/chip) in the top chamber, followed by human primary astrocytes (5000 cells/chip) and pericytes (2500 cells/chip) seeded two days later in the bottom channel. Chips were incubated for 10 days to allow formation of the neurovascular unit, sera were applied for 2 days starting at day 8 at 1:20 dilution (4 chips/patient). We quantified BBB permeability using fluorophore tagged small and large tracers (biocytin and 70 KDa dextran) to assess paracellular and transcellular BBB permeability, respectively. In addition, we measured transendothelial electrical resistance (TEER) in the last day.
Results:
Samples from 26 participants (13 preeclampsia, 13 normotensive) were tested for their effects on the human BBB. Preeclampsia samples induced higher biocytin and 70 kDa dextran leakage (p<0.01) compared with normotensive and control media. TEER measurements were lower in preeclampsia samples compared to normotensive controls and media across all time points (p<0.01 versus control media, p<0.05 versus normotensive participants). Normotensive samples showed no differences compared to media in all experiments.
Conclusions:
Sera from preeclampsia patients in the postpartum period induced higher paracellular BBB permeability compared with normotensive postpartum controls, and possible altered transcellular permeability. Lower TEER measurements similarly suggested compromised BBB integrity and function. Our data using a novel, engineered 3D human BBB model demonstrate that preeclampsia may be associated with a dysfunctional BBB even after delivery and resolution of clinical symptoms.
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