A role for GPR55 in human placental venous endothelial cells

Abstract

Endocannabinoids and their G protein-coupled receptors have been suggested to play a key role in human pregnancy, by regulating important aspects such as implantation, decidualization, placentation and labour. G protein-coupled receptor 55 (GPR55) was previously postulated to be another cannabinoid receptor, since specific cannabinoids were shown to act independently of the classical cannabinoid receptors CB1 or CB2. Current knowledge about GPR55 expression and function in human placenta is very limited and motivated us to evaluate human placental GPR55 expression in relation to other human peripheral tissues and to analyze spatiotemporal GPR55 expression in human placenta. Gene expression analysis revealed low GPR55 levels in human placenta, when compared to spleen and lung, the organs showing highest GPR55 expression. Moreover, expression analysis showed 5.8 fold increased placental GPR55 expression at term compared to first trimester. Immunohistochemistry located GPR55 solely at the fetal endothelium of first trimester and term placenta. qPCR and immunocytochemistry consistently confirmed GPR55 expression in isolated primary placental arterial and venous endothelial cells. Incubation with L-α-lysophosphatidylinositol (LPI), the specific and functional ligand for GPR55, at a concentration of 1 μM, significantly enhanced migration of venous, but not arterial endothelial cells. LPI enhanced migration was inhibited by the GPR55 antagonist O-1918, suggesting a role of the LPI-GPR55 axis in placental venous endothelium function.

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction

“…Current knowledge about GPR55 expression and function in human placenta is very limited, gene expression analysis revealed low GPR55 levels in human placenta, when compared to spleen and lung. Moreover, expression analysis showed increased placental GPR55 expression at term compared to first trimester [38]. Therefore, the effect of THC on trophoblast functions may be mediated by other cannabinoid receptors.…”

GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation

“…We sought to bridge this gap of knowledge by exploring the signaling contributions of the orphan GPCR 55 (GPR55) (9), a lipid-sensing receptor highly enriched in self-renewing organs, including liver, spleen, and salivary glands of many mammals, such as humans (10). GPR55 signaling has predominantly been studied in pathologies associated with errant cell cycle control, such as obesity (11) and cancer (12)(13)(14).…”

“…GPR55 signaling has predominantly been studied in pathologies associated with errant cell cycle control, such as obesity (11) and cancer (12)(13)(14). In the latter, GPR55 signaling promotes cancer invasion (15,16) and directional cell migration (10). Available data also suggest a positive correlation between expression levels of GPR55 and metabolic enzymes for L-α-lysophosphatidylinositol (LPI), its endogenous ligand (17), and its tumor growth, invasiveness (18,19), and negative prognosis for survival (20).…”

“…However, evidence for GPR55 signaling in physiological contexts in any organ system is lacking beyond the LPI-induced inhibition of the differentiation of bone macrophages (21) and glucose-induced insulin secretion from pancreatic β cells (22). Here, we focused on cell fate-and function-determination by GPR55 in salivary glands because (a) bulk tissue mRNA analysis assigns GPR55 expression to salivary glands in humans (10) and (b) salivary regeneration from tissue-resident progenitors is appealing to treat xerostomia (dry mouth syndrome) upon gland degeneration in, for example, Sjögren's syndrome or after radiation therapy-induced tissue damage (23). Moreover, the spatial proximity of tissue-specific progenitors and differentiated excretory progenies calls for the existence of dual-acting signaling systems that, irrespective of being either cell-autonomous or paracrine, can control organ size to ideally fit physiological requirements of salivation.…”

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

“…Bioactivities of LPI were catalogued by Piñeiro and Falasca [7]. Further actions have since been described, such as the enhancement of human placental venous endothelial cell migration [8]. LPI also modulates ion channels [9,10] and possibly other uncharacterised receptors.…”