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Am J Physiol Heart Circ Physiol. 2016 Nov 1;311(5):H1214-H1224. doi: 10.1152/ajpheart.00316.2016. Epub 2016 Sep 16.

GLP-1 inhibits VEGFA-mediated signaling in isolated human endothelial cells and VEGFA-induced dilation of rat mesenteric arteries.

Author information

1
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
2
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Department of Biomedicine, Aarhus University, Aarhus, Denmark; and.
4
Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
5
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark; sdissing@sund.ku.dk.

Abstract

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 PLCγ 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, Nω-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 PLCγ. Ca2+ imaging of endothelial cells and rat mesenteric resistance arteries using fura-2, revealed that both GLP-1 analogs caused a reduction in VEGFA-induced Ca2+ 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 Ca2+ 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:

GLP-1R; PLCγ and eNOS; VEGFA signaling; endothelial cells; vasodilation

PMID:
27638877
DOI:
10.1152/ajpheart.00316.2016
[Indexed for MEDLINE]
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