Fig. 4.

GPER-dependent signaling events in vascular endothelial and smooth muscle cells (VSMCs). Panel A: Endothelium-dependent (NO-dependent) and -independent modes of GPER-dependent relaxation in the presence of pre-existing vascular tone or pre-treatment with GPCR vasoconstrictors (Ang II or ET-1) or PGF2α. GPER agonists such as G-1 or E2 cause vasorelaxation when administered after pre-constriction. Note in this diagram, for simplicity, GPER is depicted as being in the PM, but in fact may signal intracellularly, ie from the endosomal membrane. Panel B: Endothelium-independent GPER-dependent vasoconstriction occurs in the absence of pre-existing vascular tone or when GPER agonists (G-1 or E2) are administered before vasoconstrictor agonists and probably involves Epidermal Growth Factor Receptor (EGFR) transactivation.