Regulation of angiogenesis by hypoxia: role of the HIF system.
TL;DR: The role of HIF in developmental, adaptive and neoplastic angiogenesis, and the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype are discussed.
Abstract: The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.
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TL;DR: Molecular insights into the formation of new blood vessels are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.
Abstract: Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.
4,137 citations
Cites background from "Regulation of angiogenesis by hypox..."
...Initially, cells are oxygenated by simple diffusion of oxygen, but when tissues grow beyond the limit of oxygen diffusion, hypoxia triggers vessel growth by signaling through hypoxia-inducible transcription factors (HIFs; see accompanying review in this issu...
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TL;DR: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models and is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
3,414 citations
TL;DR: Recent insights have shed light onto VEGFR signal transduction and the interplay between different V EGFRs and VEGF co-receptors in development, adult physiology and disease.
Abstract: Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.
2,894 citations
Cites background from "Regulation of angiogenesis by hypox..."
...Hypoxia allows the stabilization of hypoxia-inducible factors (HIFs) that bind to specific promoter elements that are present in the promoter region of VEGF...
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TL;DR: The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blockingAngiogenesis is an effective strategy to treat human cancer.
Abstract: The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.
2,467 citations
TL;DR: S-nitrosylation conveys a large part of the ubiquitous influence of nitric oxide on cellular signal transduction, and provides a mechanism for redox-based physiological regulation.
Abstract: S-nitrosylation, the covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine, has emerged as an important mechanism for dynamic, post-translational regulation of most or all main classes of protein. S-nitrosylation thereby conveys a large part of the ubiquitous influence of nitric oxide (NO) on cellular signal transduction, and provides a mechanism for redox-based physiological regulation.
2,006 citations
Cites background from "Regulation of angiogenesis by hypox..."
...The coordinated transcriptional control of several genes through binding to hypoxia-responsive elements (HREs) by the α,β-heterodimeric proteins hypoxia-inducible factor (HIF)1 and 2 has an important role in regulating cellular O 2 homeostasi...
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References
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TL;DR: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells.
Abstract: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.
5,729 citations
"Regulation of angiogenesis by hypox..." refers background in this paper
...HIFs and regulation by protein hydroxylation HIF-1 is an αβ-heterodimer that was first recognized as a DNA-binding factor that mediates hypoxia-inducible activity of the erythropoietin 3′ enhance...
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TL;DR: It is shown that the interaction between human pVHL and a specific domain of the HIF-1α subunit is regulated through hydroxylation of a proline residue by an enzyme the authors have termed Hif-α prolyl-hydroxylase (HIF-PH).
Abstract: Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.
5,186 citations
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Abstract: Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
4,845 citations
TL;DR: It is shown that vascular endothelial growth factor (VEGF) probably functions as a hypoxia-inducible angiogenic factor and is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci and the clustering of capillaries alongside VEGF-producing cells.
Abstract: Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.
4,627 citations
"Regulation of angiogenesis by hypox..." refers background in this paper
...and vascular endothelial growth factor (VEGF) mRNA in tissue cultur...
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TL;DR: It is found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated, which may play a key role in mammalian oxygen sensing.
Abstract: HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
4,480 citations