Regulation of angiogenesis by hypoxia-inducible factor 1

https://doi.org/10.1016/j.critrevonc.2005.12.003Get rights and content

Abstract

Hypoxia is an imbalance between oxygen supply and demand that occurs in cancer and in ischemic cardiovascular disease. Hypoxia-inducible factor 1 (HIF-1) was originally identified as the transcription factor that mediates hypoxia-induced erythropoietin expression. More recently, the delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors. In this review, we discuss the role of HIF-1 in developmental, adaptive and pathological angiogenesis. In addition, potential therapeutic interventions involving modulation of HIF-1 activity in ischemic cardiovascular disease and cancer will be discussed.

Section snippets

O2 homeostasis

The ability to maintain O2 homeostasis is essential to the survival of all invertebrate and vertebrate species. Physiological systems have evolved to ensure the optimal oxygenation of all cells in every metazoan species [1], [2]. Compared to invertebrates, the dramatic increase in body size in humans and other vertebrates is associated with the development of a complex physiological infrastructure for O2 delivery that includes the lungs, heart, vasculature, and erythrocytes. In addition to O2,

Molecular biology of hypoxia-inducible factor 1 (HIF-1)

HIF-1 was identified and purified as a nuclear factor that was induced in hypoxic cells and bound to the cis-acting hypoxia response element (HRE) located in the 3′-flanking region of the human EPO gene, which encodes erythropoietin [11], [12]. HIF-1 is a heterodimeric transcription factor composed of a HIF-1α subunit and a HIF-1β subunit [12]. Both HIF-1 subunits are members of the basic helix-loop-helix (HLH)-containing PER-ARNT-SIM (PAS)-domain family of transcription factors [13]. The HLH

Angiogenesis and arteriogenesis

Normal angiogenesis depends on the coordination of several independent and temporally ordered processes [57], [58]. Removal of pericytes from the endothelium and destabilization of the vessel shifts endothelial cells from a stable, growth-arrested state to a plastic, proliferative phenotype (Table 3). VEGF-induced hyperpermeability allows for local extravasation of proteases and matrix components from the bloodstream. Endothelial cells proliferate and migrate through the remodeled matrix, and

Ischemic cardiovascular disease

Therapeutic angiogenesis aims to stimulate neovascularization of ischemic tissues by administration of angiogenic growth factors or DNA sequences encoding these proteins. Multiple angiogenic factors, including members of the VEGF, PDGF, and fibroblast growth factor (FGF) families, have shown promising results in preclinical studies and safety in phase I clinical trials, but they have shown either marginal or no efficacy in phase II trials [68], [69]. These outcomes suggest that in patients with

Conclusion

The regulation of angiogenesis and arteriogenesis by HIF-1 is critical for normal development and for adaptive vascular responses to ischemia/hypoxia. In ischemic cardiovascular disease, HIF-1 gene therapy may provide a mechanism to stimulate arteriogenesis and stimulate the growth of collaterals to bypass stenotic vessels [74]. In cancer, inhibition of HIF-1 may be useful in particular cancers when combined with other chemotherapeutic agents or radiation therapy [90]. Whether such agents will

Reviewers

Josef T. Prchal, Professor of Medicine and Cell Biology, 1 Baylor Plaza, 802 E, Baylor College of Medicine, Houston, TX 77030, USA.

Giovanni Melillo, Senior Investigator, Tumor Hypoxia Laboratory, Developmental Therapeutics Program, SAIC Frederick Inc., Bldg 432-Rm 218, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA.

Nanduri R. Prabhakar, Professor & Vice-Chairman, Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave,

Acknowledgements

The authors apologize for the inability to cite all of the important studies that have been performed in the field due to space limitations. Work in the authors’ laboratories is supported in part by grants from the National Institutes of Health (to G.L.S.) and by a grant-in-aid for scientific research from ministry of education, culture, sports, science and technology (to K.H.).

Kiichi Hirota, M.D., Ph.D. is a graduate of Kyoto University School of Medicine and Graduate School. He is currently a lecturer in the Department of Anesthesia, Kyoto University Hospital. Currrent research in his lab is focused on investigating the clinical consequences of hypoxia-induced gene expression in anesthesiology and critical care medicine.

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    Kiichi Hirota, M.D., Ph.D. is a graduate of Kyoto University School of Medicine and Graduate School. He is currently a lecturer in the Department of Anesthesia, Kyoto University Hospital. Currrent research in his lab is focused on investigating the clinical consequences of hypoxia-induced gene expression in anesthesiology and critical care medicine.

    Gregg L. Semenza, M.D., Ph.D. is director of the Vascular Biology Program of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. His lab discovered the transcription factor HIF-1 in 1992. Current research in his lab is focused on investigating the mechanisms and consequences of HIF-1 activation in cardiovascular, neoplastic, and respiratory disorders.

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