Endocrine gland-derived vascular endothelial growth factor (EG-VEGF. identical to prokincticin 1) is a novel peptide recently identified as a selective mitogen for endocrine gland endothelial cells. The present study demonstrates that EG-VEGF/prokineticin 1 and a peptide closely related to EG-VEGF. prokineticin 2, are cognate ligands of two orphan G-protein-coupled receptors designated ZAQ (=EG-VEGF/PK-R1) and 15E (EG-VEGF/PK-R2). EG-VEGF/prokineticin I and prokineticin 2 induced a transient increase in intracellular calcium ion concentration ([Ca2+)(i)) with nanomolar potency in Chinese hamster ovary (CHO) cells expressing EG-VEGF/PK-R1 and -R2 and bind to these cells with high affinity and with different receptor selectivity. EG-VEGF/prokincticins provoke rapid phosphorylation of p44/42 MAP kinase and DNA synthesis in the bovine adrenal capillary endothelial cells (BACE). The mRNAs of both EG-VEGF/PK-R1 and -R2 were expressed in BACE. The identification of the receptors for EGVEGF/prokineticins may provide a novel molecular basis for the regulation of angiogenesis in endocrine glands. (C) 2002 Elsevier Science (USA). All rights reserved.