Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors.

Abstract

Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1alpha mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1alpha/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1alpha, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1alpha/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1alpha/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1alpha/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.

• Authors: Midori Yamakawa, Louis X Liu, Taro Date, Adam J Belanger, Karen A Vincent, Geoffrey Y Akita, Takayuki Kuriyama, Seng H Cheng, Richard J Gregory, Canwen Jiang
• Journal: Circulation research (Circ Res) Vol. 93 Issue 7 Pg. 664-73 (Oct 03 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 12958144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Angiopoietin-2
• Angiopoietins
• DNA-Binding Proteins
• Endothelial Growth Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intercellular Signaling Peptides and Proteins
• Lymphokines
• Nuclear Proteins
• PGF protein, human
• Platelet-Derived Growth Factor
• Pregnancy Proteins
• RNA, Messenger
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• angiopoietin 4
• Placenta Growth Factor
• Receptor Protein-Tyrosine Kinases
• Receptor, TIE-2
• Vascular Endothelial Growth Factor Receptor-1
• CASP3 protein, human
• Caspase 3
• Caspases
• Deferoxamine

Topics

• Angiogenesis Inducing Agents (genetics, metabolism)
• Angiopoietin-2
• Angiopoietins
• Apoptosis (drug effects)
• Blood Vessels (drug effects, growth & development)
• Caspase 3
• Caspases (metabolism)
• Cell Division (drug effects)
• Cell Hypoxia
• Cell Membrane Permeability (drug effects)
• Cell Movement (drug effects)
• Cells, Cultured
• DNA-Binding Proteins (genetics, physiology)
• Deferoxamine (pharmacology)
• Endothelial Growth Factors (genetics, metabolism)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Enzyme Activation (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation (drug effects)
• Genetic Vectors (administration & dosage, genetics)
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intercellular Signaling Peptides and Proteins (genetics, metabolism, pharmacology)
• Lymphokines (genetics, metabolism)
• Nuclear Proteins (genetics, physiology)
• Placenta Growth Factor
• Platelet-Derived Growth Factor (genetics, metabolism)
• Pregnancy Proteins (genetics, metabolism)
• RNA, Messenger (drug effects, genetics, metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Receptor, TIE-2
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1 (genetics, metabolism)
• Vascular Endothelial Growth Factors