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

Walker, D. J. and 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, 224, pp. 105-114. (doi: 10.1016/j.cbpb.2018.01.007) (PMID:29409968) (PMCID:PMC6078907)

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.

• Item Type: Articles
• Additional Information: This work was supported by a Wellcome Trust project grant 088032/Z/08/Z to SCL.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Walker, Dr David
• Authors: Walker, D. J., and Land, S. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Comparative Biochemistry and Physiology. Part B: Biochemistry and Molecular Biology
• Publisher: Elsevier
• ISSN: 1096-4959
• ISSN (Online): 1879-1107
• Published Online: 01 February 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Comparative Biochemistry and Physiology. Part B: Biochemistry and Molecular Biology 224: 105-114
• Publisher Policy: Reproduced under a Creative Commons License