Differential activation of vascular genes by hypoxia in primary endothelial cells.
Changes in the local environment, such as reduced oxygen tension (hypoxia), elicit transcriptional activation of a variety of genes in mammalian cells. Here we have analyzed the effect of hypoxia in different vascular endothelial cells (ECs) with emphasis on hypoxia-regulated transcription factors and genes of importance for blood vessel dynamics. While hypoxia induced the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in all endothelial cells tested, the closely related HIF-2alpha protein was markedly induced in microvascular/capillary endothelial cells, but only weakly or not at all in artery and vein endothelial cells. Furthermore, microvascular/capillary endothelial cells responded to hypoxia with increased number of transcripts encoding vascular endothelial growth factor-A (VEGF-A), VEGF receptor-2, the angiopoietin receptor Tie2, platelet-derived growth factor-B (PDGF-B), and inducible nitric oxide synthase (iNOS). In vein endothelial cells, hypoxia instead increased transcripts encoding lymphatic vascular components VEGF-C, -D, and VEGF receptor-3. Finally, reduced VEGF receptor levels and phosphorylation indicated establishment of a functional autocrine VEGF-A loop in hypoxic endothelial cells. Our results show that endothelial cells, derived from different vascular beds, mount different transcriptional responses to changes in oxygen tension.
Nilsson
Ingrid
I
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Shibuya
Masabumi
M
Wennström
Stefan
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D000077214:Becaplermin; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D015687:Cell Hypoxia; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007231:Infant, Newborn; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000077214:Becaplermin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C496319:NOS2 protein, human