GLP‐1 and its Analogue Liraglutide Affects Human Endothelial Cell Signaling by Reducing VEGF‐A Induced Ca²⁺ Signaling and Activating Protein Kinases

Abstract

GLP‐1 is a gut hormone and has been in focus for its role in response to food intake. An analogue of GLP‐1 has been constructed by adding a palmitoyl chain to the GLP‐1 peptide making it adhere to albumin. Here we have explored the potential roles of GLP‐1 and Liraglutide in vascular function by studying signaling in human dermal endothelial cells (HDMEC), human umbilical vein endothelial cells (HUVEC) and rat mesenteric resistance arteries. We found that HDMEC expresses the GLP‐1R by use of RT‐PCR. By use of Ca2+ imaging we found that preincubation with GLP‐1 (500 nM) caused a reduction in VEGF‐A (25 ng/ml) induced Ca2+ signaling due to a reduction in phosphorylation of PLCγ and that GLP‐1 causes phosphorylation of Src, Akt, ERK 1/2 and p38. In HUVEC, VEGF‐A (3 h, 20 ng/ml) causes a 2 times upregulation of mRNA for I‐CAM which is attenuated by 20% in the presence of Liraglutide (100 nM) and a 5 times upregulation of mRNA for V‐CAM which is attenuated 25% by Liraglutid. Liraglutide, but not GLP‐1, caused a small transient increase in [Ca2+]i. Our data are consistent with the GLP‐1 signaling being evoked through an enhanced Gs/βγ signaling since Gi inhibition with pertussis toxin elicits a similar response by favoring the Gs/βγ signaling pathway. The attenuating responses on VEGF‐induced Ca2+ transients and VEGF‐induced mRNA expression for surface proteins implicate that GLP‐1 signaling could affect endothelial cell function in relation to inflammatory processes.