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Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells : implications for co-ordinated airway and vascular branching in lung development

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Date
10/2018
Author
Walker, David J.
Land, Stephen C.
Keywords
Cardio-pulmonary system
Fibroblast growth factor-10
Gas exchange
Hypoxia inducible factor
Lung development
Symmorphosis
QH301 Biology
QP Physiology
Biochemistry
Physiology
Molecular Biology
NDAS
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Abstract
Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3′ sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.
Citation
Walker , D J & Land , S C 2018 , ' Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells : implications for co-ordinated airway and vascular branching in lung development ' , Comparative Biochemistry and Physiology Part - B: Biochemistry and Molecular Biology , vol. 224 , pp. 105-114 . https://doi.org/10.1016/j.cbpb.2018.01.007
Publication
Comparative Biochemistry and Physiology Part - B: Biochemistry and Molecular Biology
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.cbpb.2018.01.007
ISSN
1096-4959
Type
Journal article
Rights
© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Description
This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/13130

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