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Title: A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

Abstract

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by themore » ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black-Right-Pointing-Pointer Endothelial VEGFR levels are modulated during this response. Black-Right-Pointing-Pointer The cell regulates VEGF-A bioavailability and cell survival. Black-Right-Pointing-Pointer This may partly underlie endothelial dysfunction seen in many pathologies.« less

Authors:
;  [1];  [2]; ; ;  [1];  [2];  [1]
  1. Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)
  2. Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom)
Publication Date:
OSTI Identifier:
22212612
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 318; Journal Issue: 18; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; BIOLOGICAL AVAILABILITY; CELL PROLIFERATION; FIBROBLASTS; GROWTH FACTORS; IN VITRO; PATHOLOGY; PHOSPHOTRANSFERASES; RECEPTORS; TRANSFERRIN; TYROSINE; URACILS; VEINS

Citation Formats

Latham, Antony M., Odell, Adam F., Mughal, Nadeem A., Issitt, Theo, Ulyatt, Clare, Walker, John H., Homer-Vanniasinkam, Shervanthi, and Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A. United States: N. p., 2012. Web. doi:10.1016/J.YEXCR.2012.06.023.
Latham, Antony M., Odell, Adam F., Mughal, Nadeem A., Issitt, Theo, Ulyatt, Clare, Walker, John H., Homer-Vanniasinkam, Shervanthi, & Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A. United States. doi:10.1016/J.YEXCR.2012.06.023.
Latham, Antony M., Odell, Adam F., Mughal, Nadeem A., Issitt, Theo, Ulyatt, Clare, Walker, John H., Homer-Vanniasinkam, Shervanthi, and Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk. Thu . "A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A". United States. doi:10.1016/J.YEXCR.2012.06.023.
@article{osti_22212612,
title = {A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A},
author = {Latham, Antony M. and Odell, Adam F. and Mughal, Nadeem A. and Issitt, Theo and Ulyatt, Clare and Walker, John H. and Homer-Vanniasinkam, Shervanthi and Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk},
abstractNote = {Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black-Right-Pointing-Pointer Endothelial VEGFR levels are modulated during this response. Black-Right-Pointing-Pointer The cell regulates VEGF-A bioavailability and cell survival. Black-Right-Pointing-Pointer This may partly underlie endothelial dysfunction seen in many pathologies.},
doi = {10.1016/J.YEXCR.2012.06.023},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 18,
volume = 318,
place = {United States},
year = {2012},
month = {11}
}