ittle is known about the complex interactions among the 3 ERs in different cell systems, work by Ding et al has demonstrated opposing actions of ERa and GPR30 on ERK phosphorylation in cultured vascular smooth muscle cells. Cultured VSMCs with low levels of GPR30 expression showed inhibition of ERK phosphorylation in presence of E2, presumably mediated through the classical ERs. Transfection with GPR30, however, reversed these effects with E2-induced ERK phosphorylation, suggesting contradictory effects of GPR30 and classical ERs on the ERK pathway. Another study by Gao et al has recently shown opposing effects of GPR30 and classical E2 signaling on cell proliferation in mouse uterine tissue involving modulation of ERK phosphorylation. In a similar vein, our results indicate GPR30 Regulates Endothelial Inflammation opposing effects of GPR30 and the classical ERs in regulating 18519091 the endothelial inflammatory response. Relative expression of the 3 ERs may determine the precise biological effects of exogenous E2 administration in such a system, with beneficial anti-inflammatory effects associated with the increased presence of functional GPR30. 10 GPR30 Regulates Endothelial Inflammation The potential limitations of our study include the use of a single cell type, namely, HUVECs and a single pro-inflammatory cytokine, TNF. Given the differences in endothelial cells from different vascular beds, future work needs to examine the roles of GPR30 in other endothelial cell types to better understand its roles in inflammatory conditions affecting different tissues and organs. Similarly, the antiinflammatory effects observed on TNF stimulation need to be validated in the context of other proinflammatory stimuli, 18024992 namely, cytokines, chemokines and/or oxidized low density lipoprotein. Based on the potential anti-inflammatory role of GPR30, further studies of this novel estrogen receptor are needed to understand the complexity of vascular estrogen signaling. Future research in this area can lead to the development of receptorspecific targeted approaches to harness the beneficial estrogen effects while potentially minimizing the harmful side-effects. ~~ ~~ Integrins are non-covalently linked heterodimeric transmembrane receptors, present on most eukaryotic cells. They integrate signals provided by the extracellular matrix with intracellular signaling pathways acting in both directions across the plasma membrane. Inside-out signaling is induced by conformational changes mediated by the cytoplasmic and transmembrane domains of integrins. This subsequently influences ligand-binding affinities of the extracellular domains which, among others, regulates adhesion, cytoskeletal reorganization, cell proliferation, differentiation, or apoptosis as outside-in signaling processes. Within metazoans integrins exhibit group-specific evolutionary differences in structure and subunit composition. Primitive bilateria have two integrin abheterodimers, in Caenorhabditis elegans formed by one b- and two asubunits. Vertebrates have an expanded set of integrins, e.g. mammals have 8 b- and 18 a-subunits, known to assemble 24 distinct integrins. The extracellular domains of integrins recognize short peptide motifs as ligands, whose 
binding is specified by both subunits of a given ab-heterodimer. The intracellular domains of integrins are small and comprise no intrinsic catalytic MedChemExpress SB-366791 activity. Thus signals are transmitted through direct or indirect associations of the intracellular d
