RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Ahmad F. Alghanem, Emma L. Wilkinson, Maxine S. Emmett, Mohammad A. Aljasir, Katherine Holmes, Beverley A. Rothermel, Victoria A. Simms, Victoria L. Heath, Michael J. Cross

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.

Original languageEnglish (US)
Pages (from-to)1-18
Number of pages18
JournalAngiogenesis
DOIs
StateAccepted/In press - Mar 7 2017

Fingerprint

Vascular Endothelial Growth Factor Receptor-2
Cell Polarity
Endothelial cells
Cell Movement
Endothelial Cells
Calcineurin
Vascular Endothelial Growth Factor A
Protein Isoforms
Cell Physiological Phenomena
Morpholinos
Physiology
Gene Silencing
Zebrafish
Transcription
Morphogenesis
Small Interfering RNA
Blood Vessels
Vertebrates
Genes
Tissue

Keywords

  • Angiogenesis
  • Endothelial
  • Migration
  • Polarisation
  • RCAN1
  • VEGFR-2

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Cite this

Alghanem, A. F., Wilkinson, E. L., Emmett, M. S., Aljasir, M. A., Holmes, K., Rothermel, B. A., ... Cross, M. J. (Accepted/In press). RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis, 1-18. https://doi.org/10.1007/s10456-017-9542-0

RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. / Alghanem, Ahmad F.; Wilkinson, Emma L.; Emmett, Maxine S.; Aljasir, Mohammad A.; Holmes, Katherine; Rothermel, Beverley A.; Simms, Victoria A.; Heath, Victoria L.; Cross, Michael J.

In: Angiogenesis, 07.03.2017, p. 1-18.

Research output: Contribution to journalArticle

Alghanem, AF, Wilkinson, EL, Emmett, MS, Aljasir, MA, Holmes, K, Rothermel, BA, Simms, VA, Heath, VL & Cross, MJ 2017, 'RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells', Angiogenesis, pp. 1-18. https://doi.org/10.1007/s10456-017-9542-0
Alghanem, Ahmad F. ; Wilkinson, Emma L. ; Emmett, Maxine S. ; Aljasir, Mohammad A. ; Holmes, Katherine ; Rothermel, Beverley A. ; Simms, Victoria A. ; Heath, Victoria L. ; Cross, Michael J. / RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. In: Angiogenesis. 2017 ; pp. 1-18.
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