Effects of vascular endothelial growth factor on endothelin-1 production by human lung microvascular endothelial cells in vitro

Aims: Increased endothelin-1 (ET-1) is a hallmark of pulmonary arterial hypertension (PAH). and contributes to its pathogenesis. The factors controlling ET-1 in PAH are poorly understood. Combined with other stimuli, vascular endothelial growth factor (VEGF) blockade results in PAH-like lesions in animal models, and has been associated with PAH in humans. The effects of VEGF on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LB2) are unknown. Main methods: We exposed HMVEC-LB2 in-vitro to human VEGF-121 (40 ng/mL) in serum-free medium for 711, in the absence or presence of the VEGF receptor antagonist, SU5416 (3 and 10 mu M). ET-1 production was measured in the supernatant. Phosphorylation of VEGF receptor 2 (VEGFR2) was measured by Western blotting after exposure to VEGF without or with SU5416 for 5 and 10 mm. Key findings: VEGF effectively caused VEGFR2 phosphorylation, which was blocked by SU5416. VEGF decreased ET-I production by at least 29%. In the absence of VEGF, SU5416 increased ET-1 production, by 16% at 10 mu M and SU5416 was able to completely abolish the VEGF effect on ET-1 production. Significance: VEGF may promote vascular health by decreasing ET-1 production in HVMEC-LB1. Blockade of VEGF signaling by SU5416 increases ET-1 levels. The role of VEGF in modulating endothelin production in PAH deserves further study. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecornmons.org/licenses/by-nc-nd/3.0/).