Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro.

Autor: Nauta TD; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Room 11W53, 1081 HV, Amsterdam, The Netherlands.; A-Skin Nederland BV, De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands., van den Broek M; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Room 11W53, 1081 HV, Amsterdam, The Netherlands.; A-Skin Nederland BV, De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands., Gibbs S; Department of Dermatology, VU University Medical Center, Amsterdam, The Netherlands.; Departments of Oral Cell Biology and Dental Material Sciences, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands., van der Pouw-Kraan TC; Department of Molecular Cell Biology and Immunology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands., Oudejans CB; Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands., van Hinsbergh VW; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Room 11W53, 1081 HV, Amsterdam, The Netherlands., Koolwijk P; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Room 11W53, 1081 HV, Amsterdam, The Netherlands. p.koolwijk@vumc.nl.
Jazyk: angličtina
Zdroj: Angiogenesis [Angiogenesis] 2017 Feb; Vol. 20 (1), pp. 39-54. Date of Electronic Publication: 2016 Oct 03.
DOI: 10.1007/s10456-016-9527-4
Abstrakt: During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds.
Competing Interests: The authors declare no conflict of interest. S. Gibbs is co-founder and shareholder of A-Skin BV, a university spin out (SME) company.
Databáze: MEDLINE
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