Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), has been found to stimulate angiogenesis both in vivo and in vitro. However, the effect of ghrelin upon angiogenesis, and the corresponding mechanisms of ghrelin therein, in human coronary artery endothelial cells (HCAECs) under hypoxia is still unknown. Our study found that ghrelin significantly increased HCAECs proliferation, migration, in vitro angiogenesis, and microvessel sprouting from the aortic ring under hypoxic conditions. The ghrelin-induced angiogenic process was accompanied by vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and endothelial-specific receptor tyrosine kinase (Tie2) expressions. In addition, this angiogenic effect was almost completely inhibited by Ang-2 RNAi and Tie2 RNAi. Pretreatment with the GHSR1a blocker [D-Lys3]-GHRP-6 abolished ghrelin-induced VEGF, Ang-1, Ang-2 and Tie2 expressions and in vitro angiogenesis. In conclusion, this is the first demonstration that ghrelin stimulates HCAECs in vitro angiogenesis through GHSR1a-mediated VEGF, Ang-1, Ang-2 and Tie2 pathways under hypoxic conditions. It indicated that ghrelin might play an important role in myocardial angiogenesis after ischemic injury.