Endocrine Abstracts

Background: Kisspeptin is a neuropeptide central to the regulation of gonadotrophin secretion but recent studies have suggested more diverse roles in human physiology. Kisspeptin is a potent inhibitor of tumour metastasis and plays a role in placentation, both processes involving angiogenesis. In addition, Kisspeptin and its receptor, GPR54, have been identified in human blood vessels including aorta, coronary artery and umbilical vein, where they mediate vasoconstriction. We, therefore, hypothesised that kisspeptin plays a role in regulating angiogenesis and aimed to examine its effects in vitro on key angiogenic steps.

Methods: The effects of kisspeptin on in vitro angiogenesis were examined in HUVECS using a tube formation assay, cell migration (wound healing) assay and cell proliferation (BrdU incorporation) assay with concentrations of kisspeptin ranging from 100 pM to 1 μM.

Results: Kisspeptin did not impair endothelial cell viability but induced a concentration-dependent inhibition of tube formation at 8 h (P<0.05) with effects persisting at 24 h (P<0.05). Likewise kisspeptin inhibited cell proliferation at similar concentrations (P<0.01). Concentration-dependent inhibition of cell migration was observed with maximal effects at 1 nM (P<0.05). This effect was reversed by administration of a GPR54 receptor antagonist (100 nM 234; P<0.05) and by Gq-Src-PI(3)K-ERK pathway inhibitors (100 nM YM254980; 5 μM PP2; 1 μM AG1478; 20 μM PD98059), but not by PKC inhibitors (1 μM Go6983; 1 μM Ro-31-8220; 1 μM staurosporin).

Conclusions: Kisspeptin inhibits key stages of angiogenesis in vitro. Thus kisspeptin may play a crucial role in regulating angiogenesis in tissues where this process is tightly controlled including the placenta and in tumour formation. The kisspeptin/GPR54 system may offer a potential new therapeutic target to regulate angiogenesis.

This work was supported by PiggyBankKids/Jennifer Brown and the Medical Research Council.