Working Paper Article Version 1 This version is not peer-reviewed

Prostaglandin D2 Strengthens Human Endothelial Barrier by Activation of E-type Receptor 4

Version 1 : Received: 10 June 2020 / Approved: 12 June 2020 / Online: 12 June 2020 (05:05:37 CEST)

How to cite: Rittchen, S.; Rohrer, K.; Platzer, W.; Knuplez, E.; Atallah, R.; Sharma, N.; Nagaraj, C.; Heinemann, A. Prostaglandin D2 Strengthens Human Endothelial Barrier by Activation of E-type Receptor 4. Preprints 2020, 2020060142 Rittchen, S.; Rohrer, K.; Platzer, W.; Knuplez, E.; Atallah, R.; Sharma, N.; Nagaraj, C.; Heinemann, A. Prostaglandin D2 Strengthens Human Endothelial Barrier by Activation of E-type Receptor 4. Preprints 2020, 2020060142

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. It has been suggested 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. These data demonstrate a novel mechanism by which PGD2 may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.

Subject Areas

Prostaglandin D2; BW245c; prostanoid signalling; EP4 receptor; endothelial barrier; barrier disruption; microvascular endothelium

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