Vasoactive peptides upregulate mRNA expression and secretion of vascular endothelial growth factor in human airway smooth muscle cells |
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Authors: | Vijay K T Alagappan Anna Willems-Widyastuti Ann L B Seynhaeve Ingrid M Garrelds Timo L M ten Hagen Pramod R Saxena Hari S Sharma |
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Institution: | (1) Cardiopulmonary and Molecular Biology Lab, Departments of Pharmacology, University Medical Centre Rotterdam, The Netherlands;(2) Surgical Oncology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands |
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Abstract: | Airway remodeling and associated angiogenesis are documented features of asthma, of which the molecular mechanisms are not
fully understood. Angiotensin (ANG)II and endothelin (ET)-1 are potent vasoconstricting circulatory hormones implicated in
asthma. We investigated the effects of ANG II and ET-1 on human airway smooth muscle (ASM) cells proliferation and growth
and examined the mRNA expression and release of the angiogenic peptide, vascular endothelial growth factor (VEGF). Serum deprived
(48 h) human ASM cells were incubated with ANG II (100 nM) or ET-1 (10nM) for 30 min, 1, 2, 4, 8, 16, and 24 h and the endogenous synthesis of VEGF was examined in relation to control cells receiving
serum free culture medium. ET-1 induced time dependent DNA biosynthesis as determined by 3H]-thymidine incorporation assay. Using northern blot hybridization, we detected two mRNA species of 3.9 and 1.7 kb encoding
VEGF in the cultured smooth muscle cells. Both ANG II and ET-1 induced the mRNA expression (two-to threefold) and secretion
(1.8-to 2.8-fold) of VEGF reaching maximal levels between 4–8 h of incubation. Induced expression and release of VEGF declined
after 8 h of ANG II incubation while levels remained elevated in the case of ET-1. The conditioned medium derived from ET-1-treated
ASM cells induced 3H]-thymidine incorporation and cell number in porcine pulmonary artery endothelial as well as human umbilical vein endothelial
cells. Moreover, the VEGF tyrosine kinase receptor inhibitor blocked the conditioned medium induced mitogenesis in endothelial
cells. Our results suggest a potential role for ANG II and ET-1 in ASM cell growth and upregulation of VEGF that may participate
in endothelial cell proliferation via paracrine mechanisms and thus causing pathological angiogenesis and vascular remodelling
seen during asthma. |
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Keywords: | Angiotensin II endothelin-1 airway smooth muscle vascular endothelial growth factor angiogenesis and asthma |
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