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Our hypothesis was that GLP-1 released from intestinal l-cells modulates processes related to PLC\u03b3 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\u201390% of maximum contraction, VEGFA (25 ng\/ml) caused a small and gradual relaxation (28.9 \u00b1 3.9%). Pretreatment of arteries with either GLP-1(1\u201336) (500 nM) or GLP-1(7\u201336) (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\u03c9-nitro-l-arginine methyl ester (100 \u03bcM). In vivo studies on male Wistar rats also revealed that GLP-1(7\u201336) inhibited VEGFA-induced vasodilation of the same arteries. In isolated endothelial cells, GLP-1(1\u201336) and GLP-1(7\u201336) caused a reduction in VEGFA-induced phosphorylation of PLC\u03b3. Ca<jats:sup>2+<\/jats:sup>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<jats:sup>2+<\/jats:sup>signaling. GLP-1(1\u201336) 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<jats:sup>2+<\/jats:sup>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.<\/jats:p>","DOI":"10.1152\/ajpheart.00316.2016","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T02:49:33Z","timestamp":1474080573000},"page":"H1214-H1224","source":"Crossref","is-referenced-by-count":16,"title":["GLP-1 inhibits VEGFA-mediated signaling in isolated human endothelial cells and VEGFA-induced dilation of rat mesenteric arteries"],"prefix":"10.1152","volume":"311","author":[{"given":"Cecilie","family":"Egholm","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makhala Michell","family":"Khammy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 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