Publication Date:
2016-11-03
Description:
We investigated the acute effects of glucagon-like peptide-1 (GLP-1), GLP-1(1–36), and GLP-1(7–36) on vascular endothelial growth factor-A (VEGFA)-induced endothelium-dependent signaling and vasodilation. Our hypothesis was that GLP-1 released from intestinal l -cells modulates processes related to PLC activation, Src, and endothelial NOS (eNOS) signaling, thereby controlling endothelial vessel tone. By using RT-PCR analysis, we found mRNA for the GLP-1 receptor (GLP-1R) in human dermal microvascular endothelial cells (HDMEC), human retinal microvascular endothelial cells, and rat arteries. In isolated rat mesenteric resistance arteries precontracted with the thromboxane analog U46619 to 80–90% of maximum contraction, VEGFA (25 ng/ml) caused a small and gradual relaxation (28.9 ± 3.9%). Pretreatment of arteries with either GLP-1(1–36) (500 nM) or GLP-1(7–36) (1 nM) abolished the VEGFA-induced relaxation. VEGFA-induced relaxations were also inhibited in endothelial-denuded arteries and in arteries pretreated with the nitric oxide synthase (NOS) inhibitor, N-nitro- l -arginine methyl ester (100 μM). In vivo studies on male Wistar rats also revealed that GLP-1(7–36) inhibited VEGFA-induced vasodilation of the same arteries. In isolated endothelial cells, GLP-1(1–36) and GLP-1(7–36) caused a reduction in VEGFA-induced phosphorylation of PLC. Ca 2+ imaging of endothelial cells and rat mesenteric resistance arteries using fura-2, revealed that both GLP-1 analogs caused a reduction in VEGFA-induced Ca 2+ signaling. GLP-1(1–36) also reduced VEGFA-induced eNOS phosphorylation in HDMEC. In conclusion, GLP-1 reduced relaxation induced by VEGFA in resistance arteries by inhibiting VEGFR2-mediated Ca 2+ signaling and endothelial NO synthesis. GLP-1, on its own, also induced phosphorylation of Src and ERK1/2 that can lead to proliferation and is implicated in vessel permeability.
Keywords:
Vascular Biology and Microcirculation
Print ISSN:
0363-6135
Electronic ISSN:
1522-1539
Topics:
Medicine
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