1. Prostaglandin D2 strengthens human endothelial barrier by activation of E-type receptor 4
- Author
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Walter Klepetko, Chandran Nagaraj, Kathrin Rohrer, Katharina Sinn, Eva Knuplez, Leigh M. Marsh, Reham Atallah, Thomas Bärnthaler, Neha Sharma, Sonja Rittchen, Wolfgang Platzer, and Akos Heinemann
- Subjects
0301 basic medicine ,Pharmacology ,integumentary system ,Chemistry ,EP4 Receptor ,Inflammation ,Lipid signaling ,Biochemistry ,Extravasation ,Cell biology ,Endothelial stem cell ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,lipids (amino acids, peptides, and proteins) ,Prostaglandin D2 ,medicine.symptom ,Receptor ,Barrier function - Abstract
Life-threatening inflammatory conditions such as acute respiratory distress syndrome or sepsis often go hand in hand with severe vascular leakage. During inflammation, endothelial cell integrity and intact barrier function are crucial to limit leukocyte and plasma extravasation. Prostaglandin D2 (PGD2) is a potent inflammatory lipid mediator with vasoactive properties. Previous studies suggest that PGD2 is involved in the regulation of endothelial barrier function; however, it is unclear whether this is also true for primary human pulmonary microvascular endothelial cells. Furthermore, as PGD2 is a highly promiscuous ligand, we set out to determine which receptors are important in human pulmonary endothelial cells. In the current study, we found that PGD2 and the DP1 agonist BW245c potently strengthened pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Yet surprisingly, these effects were mediated only to a negligible extent via DP1 receptor activation. In contrast, we observed that the EP4 receptor was most important and mediated the barrier enhancement by PGD2 and BW245c. Stimulation with PGE2 or PGD2 reduced AKT phosphorylation which could be reversed by prior blockade of EP4 receptors. These data demonstrate a novel mechanism by which PGD2 may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.
- Published
- 2020