Sigma‐1 Receptor Agonists Compromise Barrier Function of Endothelial Cell Monolayers with Differential Impact on Cells Derived from Cardiac or Dermal Microcirculation and Dermal Lymphatics

Sigma‐1 receptors are chaperone proteins in the endoplasmic reticulum known to modulate calcium signaling through the IP3 receptor. We recently demonstrated the presence of these receptors in the lymphatic vessels. In the current study we tested the hypothesis that Sigma‐1 receptors are present and functional in human cardiac microvascular endothelial cells (HCMEC), dermal microvascular endothelial cells (HDMEC) and human dermal lymphatic endothelial cells (HDLEC). Western blotting and immunofluorescence labeling were performed to verify expression of the Sigma‐1 receptor in these cell types. The cells were treated with the selective sigma‐1 receptor agonist, afobazole, or dehydroepiandrosterone (DHEA), which also can activate sigma‐1 receptors. Transendothelial electrical resistance (TER) was used as an index of barrier function. Western blot analysis confirmed expression of the Sigma‐1 receptor in HCMEC, HDMEC, and HDLEC. Immunofluorescence confocal microscopy studies showed that Sigma‐1 localization was largely punctate and perinuclear, with a similar pattern seen for endoplasmic reticulum. In HCMEC or HDLEC, DHEA and afobazole both decreased TER. However, in HDMEC, neither agonist caused a significant decrease in barrier function. The data demonstrates that Sigma‐1 receptors are indeed present in HCEC, HDEC and ADLEC, but functional responses to Sigma‐1 receptor agonists vary between the different endothelial cell sources. Support or Funding Information Supported by NIH grant R01HL098215 and APS Frontiers Fellowship.