Protective role of FKBP51 in calcium entry-induced endothelial barrier disruption. (January 2018)

• Record Type: Journal Article
• Authors: Hamilton, Caleb L.; Kadeba, Pierre I.; Vasauskas, Audrey A.; Solodushko, Viktoriya; McClinton, Anna K.; Alexeyev, Mikhail; Scammell, Jonathan G.; Cioffi, Donna L.
• Is Part Of: Pulmonary circulation. Volume 8:Number 1(2018)
• Publication Date: 2018-01
• Subjects: FKBP51 -- ISOC -- calcium -- endothelial barrier -- cytoskeleton; Pulmonary circulation -- Periodicals; Pulmonary circulation; Electronic journals -- Sciences; Periodicals; 616.24005
• DOI: 10.1177/2045893217749987
• Languages: English
• ISSNs: 2045-8932

Abstract

Pulmonary artery endothelial cells (PAECs) express a cation current, I SOC (store-operated calcium entry current), which when activated permits calcium entry leading to inter-endothelial cell gap formation. The large molecular weight immunophilin FKBP51 inhibits I SOC but not other calcium entry pathways in PAECs. However, it is unknown whether FKBP51-mediated inhibition of I SOC is sufficient to protect the endothelial barrier from calcium entry-induced disruption. The major objective of this study was to determine whether FKBP51-mediated inhibition of I SOC leads to decreased calcium entry-induced inter-endothelial gap formation and thus preservation of the endothelial barrier. Here, we measured the effects of thapsigargin-induced I SOC on the endothelial barrier in control and FKBP51 overexpressing PAECs. FKBP51 overexpression decreased actin stress fiber and inter-endothelial cell gap formation in addition to attenuating the decrease in resistance observed with control cells using electric cell-substrate impedance sensing. Finally, the thapsigargin-induced increase in dextran flux was abolished in FKBP51 overexpressing PAECs. We then measured endothelial permeability in perfused lungs of FKBP51 knockout (FKBP51 –/– ) mice and observed increased calcium entry-induced permeability compared to wild-type mice. To begin to dissect the mechanism underlying the FKBP51-mediated inhibition of I SOC, a second goal of this study was to determine the role of the microtubule network. We observed that FKBP51 overexpressing PAECs exhibited increased microtubule polymerization that is critical for inhibition of I SOC by FKBP51. Overall, we have identified FKBP51 as a novel regulator of endothelial barrier integrity, and these findings are significant as they reveal a protective mechanism for endothelium against calcium entry-induced disruption.