Regulation of angiogenesis by hypoxia-inducible factor 1

Regulation of angiogenesis by hypoxia-inducible factor 1

Critical Reviews in Oncology/Hematology 59 (2006) 15–26 Regulation of angiogenesis by hypoxia-inducible factor 1 Kiichi Hirota a , Gregg L. Semenza b...

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Critical Reviews in Oncology/Hematology 59 (2006) 15–26

Regulation of angiogenesis by hypoxia-inducible factor 1 Kiichi Hirota a , Gregg L. Semenza b,c,d,∗ a Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA d McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA b

c

Accepted 24 December 2005

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Hypoxia and angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. O2 homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Regulation of angiogenesis by O2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transcriptional responses to hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Molecular biology of hypoxia-inducible factor 1 (HIF-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. HIF-1 activity under hypoxic conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. HIF-1 activity under non-hypoxic conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. HIF-1 activity in cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Involvement of HIF-1 in angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Angiogenesis and arteriogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vascular phenotype of HIF-1-deficient mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Regulation of genes encoding angiogenic growth factors by HIF-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Cell-autonomous effects of HIF-1 in vascular endothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. HIF-2␣ and HIF-3␣/IPAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic implications of HIF-1-regulated angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Ischemic cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Hypoxia is an imbalance between oxygen supply and demand that occurs in cancer and in ischemic cardiovascular disease. Hypoxiainducible 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. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Arteriogenesis; Cancer; HIF-1; Ischemia; Prolyl hydroxylase; Vascular endothelial growth factor ∗

Corresponding author at: 733 North Broadway, Suite 671, Baltimore, MD 21205, USA. Tel.: +1 410 955 1619; fax: +1 443 287 5618. E-mail address: [email protected] (G.L. Semenza).

1040-8428/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2005.12.003

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1. Hypoxia and angiogenesis 1.1. 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 , blood vessels deliver nutrients and other molecules, remove metabolic waste, and carry immune cells to all tissues in our body. The complex development and regulation of these physiological systems provide a major basis for O2 homeostasis. 1.2. Regulation of angiogenesis by O2 The regulation of angiogenesis by hypoxia is an important component of homeostatic control mechanisms that link cardio-pulmonary-vascular oxygen supply to metabolic demand in local tissue [3,4]. Insights into the role of O2 in regulating angiogenesis came from pathophysiological studies of vascular and neoplastic disease. For example, in retinopathy of prematurity, which occurs in preterm infants that are exposed to elevated concentrations of O2 as a result of mechanical ventilation for respiratory insufficiency, development of the retinal circulation is suppressed. When mechanical ventilation is discontinued and the inspired oxygen concentration is reduced to normal levels, the retina is subjected to hypoxia, which induces pathological new vessel growth in the retina that can result in retrolental fibroplasia and partial or total loss of visual acuity [5,6]. Within tumors, the availability of O2 and nutrients is limited by competition among actively proliferating cells, and diffusion of metabolites is inhibited by high interstitial pressure [7]. In response to intratumoral hypoxia, angiogenesis-stimulating factors produced by tumor cells induce the formation of a new blood supply from the preexisting vasculature, which is critical for tumor cells to survive and proliferate in a hostile microenvironment [8–10]. In wounds, capillary injury generates a hypoxic environment, and altered oxygenation of experimental wounds alters the reconstructive angiogenic response [10]. Thus, hypoxia serves as a critical cue for both physiological and pathological angiogenesis.

2. Transcriptional responses to hypoxia 2.1. 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-1␣ subunit and a HIF-1␤ 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 and PAS domains mediate heterodimer formation between the HIF-1␣ and HIF-1␤ subunits, which is necessary for DNA binding by the basic domains [14]. In humans (and other mammals), the HIF1A, EPAS1, and HIF3A genes (Unigene accession numbers Hs.509554, Hs.468410, and Hs.420830, respectively) have been shown to encode HIF-1␣ and the structurally related proteins HIF2␣, and HIF-3␣, respectively. In contrast to HIF-1␣, HIF-2␣ (also known as endothelial PAS domain protein 1 [EPAS1], HIF-1-like factor, HIF-related factor, and member of PAS superfamily 2) and HIF-3␣ have more restricted expression patterns [15,16]. HIF-1␣ and HIF-2␣ show the greatest structural and functional similarity, as each of these proteins is hypoxia-induced, dimerizes with HIF-1␤, and mediates HRE-dependent transcriptional activity [14,17], although they regulate distinct groups of target genes in vivo [18,19]. In contrast, HIF-3␣ (also known as IPAS) appears to function as an inhibitor that is involved in the negative regulation of transcriptional responses to hypoxia [20,21]. The expression of over 40 genes is known to be activated at the transcriptional level by HIF-1 as determined by the most stringent criteria (Table 1), including the induction of gene expression in response to hypoxia, the presence of a functionally-essential HIF-1 binding site in the gene, and an effect of HIF-1 gain-of-function or loss-of-function on expression of the gene. However, a recent study of global gene expression using using DNA microarrays indicates that more than 2% of all human genes are directly or indirectly regulated by HIF-1 in arterial endothelial cells [22]. 2.2. HIF-1 activity under hypoxic conditions The regulation of gene transcription by HIF-1 represents the most well defined molecular mechanism for sensing and responding to changes in O2 concentration in metazoans. Whereas HIF-1␤ is constitutively expressed, HIF-1␣ expression increases exponentially as O2 concentration declines [23]. In order to respond rapidly to hypoxia, cells continuously synthesize, ubiquitinate, and degrade HIF-1␣ protein under non-hypoxic conditions [24–26]. Under hypoxic conditions, the degradation of HIF-1␣ is inhibited, resulting in accumulation of the protein, dimerization with HIF-1␤, binding to HREs within target genes, and activation of transcription via recruitment of the coactivators p300 and CBP [27]. Hydroxylation of two prolyl residues (Pro402 and Pro564 in human HIF-1␣) mediates interactions with the von HippelLindau (VHL) E3 ubiquitin ligase complex that targets HIF1␣ (as well as HIF-2␣ and HIF-3␣) for proteasomal degrada-

K. Hirota, G.L. Semenza / Critical Reviews in Oncology/Hematology 59 (2006) 15–26 Table 1 Genes that are directly regulated by HIF-1 Gene product

References

ABCG2 ␣1B -Adrenergic receptor Adrenomedullin Aldolase A (ALDA) Atrial natriuretic peptide Carbonic anhydrase 9 CD18 Ceruloplasmin C-MET Connective tissue growth factor CYP3A6 CXCR4 DEC1 DEC2 Ecto-5 -nucleotidase (CD73) Endocrine gland-derived VEGF Endoglin Endothelin-1 Enolase 1 ENOS Erythropoietin ETS-1 Glucose transporter 1 (GLUT1) Glyceraldehyde-3-phosphate dehydrogenase Glucose regulated protein, 94-kDa (GRP94) Heme oxygenase-1 HIF-1␣ prolyl hydroxylase PHD3 (EGLN3) HIF-1␣ prolyl hydroxylase PHD2 (EGLN1) HGTD-P ID2 Integrin ␤2 Intestinal trefoil factor Lactate dehydrogenase A (LDHA) Lactase Leptin Membrane type-1 matrix metalloproteinase Multi-drug resistance 1 (ABCB1) Myeloid cell factor 1 (MNL1) Nitric oxide synthase 2 NIP3 NUR77 p35srj (CITED2) Phosphoglycerate kinase 1 6-Phosphofructo-2-kinase/fructose-2,6bisphosphatase-3 (PFKFB3) 6-Phosphofructo-2-kinase/fructose-2,6bisphosphatase-4 (PFKFB4) Plasminogen activator inhibitor 1 Procollagen prolyl-4-hydroxylase ␣(I) ROR␣ Stromal-derived factor 1 (SDF-1) Telomerase (TERT) Transferrin Transferrin receptor Transforming growth factor ␤3 Vascular endothelial growth factor (VEGF) VEGF receptor-1 (Flt-1)

[91] [92] [93] [54,94] [95] [96] [97] [98] [99] [100] [101] [102–104] [105] [105] [106] [107] [108] [109] [110] [111] [11,14] [112] [54,94,113] [114,115] [116] [117] [118] [119] [120] [121] [97] [122] [54,110] [123] [124] [125] [126] [127] [128] [129] [130] [131] [54,94,110,132] [133,134] [135] [136] [137] [138,139] [102,140] [141] [142] [143,144] [145] [52,54,59,94] [146]

tion [28,29]. These hydroxylated residues are present within a conserved L-X-X-L-A-P motif (A, alanine; L, leucine; P, proline; X, any amino acid). The HIF-1␣ prolyl hydroxylases utilize O2 as a substrate with a Km that is slightly above

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atmospheric concentration, such that enzymatic activity is modulated by changes in O2 concentration under physiological conditions [30,31]. A family of three human HIF-1␣ prolyl hydroxylases, designated prolyl hydroxylase domaincontaining proteins (PHDs) or HIF-1␣ prolyl hydroxylases (HPHs) 1, 2, and 3, was identified and shown to be encoded by the EGLN2, EGLN1, and EGLN3 genes, respectively [31,32]. The OS-9 protein interacts with both HIF-1␣ and the prolyl hydroxylases and promotes the O2 -dependent hydroxylation of HIF-1␣ [33]. An asparaginyl residue in the transactivation domain of HIF-1␣ (Asn803 in human HIF-1␣) is hydroxylated by factor inhibiting HIF-1 (FIH-1) [34–37]. The sequence surrounding this site (Y-D-C-E-V-N-A-P in HIF-1␣ and Y-D-C-EV-N-V-P in HIF-2␣ [C, cysteine; D, aspartate; E, glutamate; N, asparagine; V, valine; Y, tyrosine]) is conserved among the vertebrates species (chick, frog, human, mouse, rat, and zebrafish) for which sequence data are available in GenBank (http://www.ncbi.nlm.nih.gov). Hydroxylation of Asn803 blocks interaction of the HIF-1␣ transactivation domain with the transcriptional coactivators CBP and p300 [35]. Vertebrate HIF-1␣ and HIF-2␣ proteins each contain one asparaginyl and two prolyl hydroxylation sites, whereas in the single C. elegans protein that is homologous to HIF-1␣ and HIF-2␣, only the prolyl hydroxylation site corresponding to Pro564 in human HIF-1␣ is conserved. The prolyl and asparaginyl hydroxylation reactions require O2 , Fe (II), and ␣-ketoglutarate (also known as 2-oxoglutarate), and generate succinate and CO2 as side-products. The prolyl hydroxylases and FIH-1 possess a double-stranded ␤-helix core and Fe (II)-binding residues that are present in other members of the dioxygenase family such as the procollagen prolyl 4-hydroxylases [38]. To study the details of the catalytic properties of the enzymes, all three human PHD enzymes and FIH-1 were expressed as recombinant proteins and analyzed using an assay based on the measurement of 14 CO2 released during the hydroxylation-coupled decarboxylation of 2-oxo[1-14 C]glutarate, adopting methods similar to those used for procollagen prolyl 4-hydroxylases [39,40]. From these studies, the biochemical properties of PHDs and FIH1 including the kinetic constants for the co-substrates have been determined in vitro. 2.3. HIF-1 activity under non-hypoxic conditions Physiological stimuli other than hypoxia can also induce HIF-1 activation and the transcription of hypoxia-inducible genes under non-hypoxic conditions. Signaling via the HER2/neu or IGF-1 receptor tyrosine kinase induces HIF1 expression by an oxygen-independent mechanism that increases the rate of HIF-1␣ protein synthesis [41,42]. IGF-1induced HIF-1␣ synthesis is dependent upon both the phosphatidylinositol 3-kinase and MAP kinase pathways [42]. In addition to growth factors, prostaglandin E2 , thrombin, angiotensin II, 5-hydroxytryptamine, acetylcholine and some

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nitric oxide (NO) donors induce HIF-1 activation under nonhypoxic conditions via these pathways [43–46]. The administration of other NO donors to non-hypoxic cells inhibits prolyl hydroxylase activity by an undetermined mechanism [47]. Under hypoxic conditions, NO inhibits the induction of HIF-1␣, a phenomenon which one group has attributed to inhibition of mitochondrial O2 consumption [48], whereas another group has provided evidence that under hypoxic conditions, NO increases the concentration of intracellular free iron, thus stimulating prolyl hydroxylase activity [49]. 2.4. HIF-1 activity in cancer cells Immunohistochemical analysis of human tumor biopsies has revealed overexpression of HIF-1␣ in common cancers [50,51]. High HIF-1␣ levels in tumors reflect the frequent presence of intratumoral hypoxia and the fact that many common genetic alterations in cancer cells affect HIF-1␣ expression (Table 2). Loss-of-function of VHL, SDH-B, SDH-C, SDH-D, or FH (subunits of succinate dehydrogenase and fumarate hydratase) blocks the ubiquitination and proteasomal degradation of HIF-1␣. Other genetic alterations dysregulate signal transduction pathways leading to increased HIF-1␣ synthesis. These data provide a molecular mechanism linking oncogene gain-of-function and tumor suppressor gene loss-offunction with tumor vascularization because HIF-1 has been shown to bind to and activate transcription of the gene encoding vascular endothelial growth factor (VEGF) [52]. HIF-1 has also been shown to regulate the expression of genes encoding glucose transporters and glycolytic enzymes [53,54]. Cancer cell energy metabolism deviates significantly from that of normal tissues. Cancer cells maintain high aerobic glycolytic rates and produce high levels of lactate and pyruvate. This phenomenon was first described in cancer more than seven decades ago [55] and is known as the Warburg effect after its discoverer. In addition, the remarkable Table 2 Mechanism of increased HIF-1␣ expression in cancer cells Alteration in tumors

Underlying molecular mechanism

Hypoxia VHL loss-of-function SDH-B loss-of-function SDH-C loss-of-function SDH-D loss-of-function FH loss-of-function p53 Loss-of-function PTEN loss-of-function TSC2 loss-of-function p14ARF loss-of-function SRC gain-of-function PI3K/AKT/mTOR gain-of-function

Ubiquitination ↓ [24,26] Ubiquitination ↓ [25,147] Ubiquitination ↓ [148–150] Ubiquitination ↓ [148–150] Ubiquitination ↓ [148–150] Ubiquitination ↓ [148–150] Ubiquitination ↓ [79] Synthesis ↑ [87,151] Synthesis ↑ [152] Nucleolar sequestration [153] Synthesis ↑; ubiquitination ↓ [154,155] Synthesis ↑ [41]

VHL: von Hippel-Lindau protein; SDH: succinate dehydrogenase; FH: fumarate hydratase; PTEN: phosphatase and tensin homolog deleted on chromosome 10; TSC: tuberous sclerosis; PI3K: phosphatidylinositol-3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin.

frequency with which common genetic alterations in cancer cells are associated with increased HIF-1␣ expression suggests that HIF-1␣ overexpression confers selective advantages that contribute to the accumulation of these mutations during tumor progression. This hypothesis is supported both by mechanistic studies in animal models of cancer and by clinical studies demonstrating that HIF-1␣ overexpression is associated with increased risk of mortality in a variety of human cancers [56]. 3. Involvement of HIF-1 in angiogenesis 3.1. 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, growtharrested 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 then they form tubes through which blood can flow. Mesenchymal cells proliferate and migrate along the new vessel and differentiate into mature pericytes. Establishment of endothelial cell quiescence, strengthening of cell–cell contacts, and elaboration of new matrix stabilize the new vessel. Arteriogenesis refers to the process by which the luminal diameter of preexisting arterioles is increased to provide collateral sources of blood flow in response to critical narrowing of a major artery. This process should be clearly distinguished from angiogenesis, which refers to the formation of capillary branches by sprouting from preexisting capillaries. Angiogenesis is important for the improvement of local tissue perfusion in order to match O2 supply and demand, which Table 3 HIF-1-regulated factors involved in different steps in angiogenesis Steps in angiogenesis

Factors

Arterial destabilization Increased vascular permeability Extracellular matrix remodeling Migration and profiferation of endothelial cells Endothelial cell sprouting Tube formation and cell-to-cell contact Recruitment of and interaction with pericytes Maintenance of vessel integrity

VEGF,PLGF,Flt-1 VEGF,Flt-1,angiopoietin-2,Tie-2 MMPs,collagen prolyl-4-hydroxylase,uPAR VEGF,PLGF,angiopoietin-1, MCP-1,PDGF,SDF-1,CXCR4 Angiopoietin-2,Tie-2 VEGF,PLGF,angiopoietin-1,integrins PDGF,PAI-1,angiopoietin-1,Tie-2

VEGF: vascular endothelial growth factor; PLGF: placental growth factor; Flt-1: fms-like tyrosine kinase; MMP: matrix metalloproteinase; uPA: urokinase plasminogen activator; MCP-1: monocyte chemoattractant protein 1; SDF-1: stromal cell-derived factor-1; PAI: plasminogen activator inhibitor.

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occurs during cell proliferation or hypertrophy. However, an increased number of capillaries in the distal vascular bed cannot compensate for obstruction of a proximal conduit vessel. 3.2. Vascular phenotype of HIF-1-deficient mice Targeted disruption of either Hif1a (encoding HIF-1␣) [54,59,94] or Arnt (encoding HIF-1␤) [60] in the mouse results in embryonic lethality at midgestation that is associated with dramatic vascular regression due to extensive endothelial cell (EC) death. In Hif1a−/− mice, defects in angiogenesis have been observed in both the yolk sac and in the developing embryo, and are associated with severe hypoxia due to lack of perfusion [61]. Conditional knock-out mice lacking HIF-1␣ expression in neural cells have marked cerebral atrophy associated with vascular regression [62]. Gain or loss of HIF-1␣ expression specifically within ECs modulates a number of important parameters of EC behavior during angiogenesis including proliferation, chemotaxis, and extracellular matrix penetration [22,63]. The vascularization of solid tumors is markedly impaired in mice with conditional knockout of the Hif1a gene in ECs [63]. The normal development of mice selectively lacking expression of HIF-1␣ in ECs is likely due to the continued expression of HIF-2␣ in these cells. 3.3. Regulation of genes encoding angiogenic growth factors by HIF-1 These genetic data indicate that HIF-1 plays critical roles in angiogenesis during embryonic development and disease pathogenesis. Angiogenesis is a complex process, involving multiple gene products expressed by different cell types, all contributing to an integrated sequence of events. Consistent with a major role for hypoxia in the overall process, many genes involved in different steps of angiogenesis are independently responsive to hypoxia in tissue culture. Examples include VEGF, angiopoietin 1 (ANGPT1) and ANGPT2, placental growth factor (PLGF), and platelet-derived growth factor B (PDGFB) and their various receptors, and genes involved in matrix metabolism, including matrix metalloproteinases, plasminogen activator receptors and inhibitors, and procollagen prolyl hydroxylase (Table 3). HIF-1 directly activates transcription of the VEGF gene by binding to an HRE [52], whereas it has not been determined whether ANGPT1, ANGPT2, PLGF, and PDGFB are direct targets of HIF-1 [64]. The regulation of these genes is remarkably cell type specific: ANGPT2 expression is induced by hypoxia in arterial ECs, repressed in arterial smooth muscle cells, and unchanged in cardiac fibroblasts and myocytes, whereas VEGF is induced by hypoxia in all four cell types [64]. 3.4. Cell-autonomous effects of HIF-1 in vascular endothelial cells In addition to controlling the production of angiogenic factors in hypoxic or ischemic tissue, HIF-1 also controls

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cell-autonomous responses to hypoxia within ECs. HIF-1 controlled VEGF production leads to autocrine signal transduction that is critical for angiogenesis [63]. Many of the biological processes in angiogenesis, extracellular matrix invasion and tube formation by ECs are stimulated under hypoxic conditions through HIF-1, which activates the transcription of scores of genes whose protein products play critical roles in these processes [22]. 3.5. HIF-2α and HIF-3α/IPAS HIF-2␣ was named endothelial PAS protein-1 (EPAS1) by one group based upon its expression in this cell type [15]. Though one study showed a defect in vascular remodeling, with abnormally fenestrated capillaries resulting in local hemorrhage [65], differing phenotypes have been observed in two other studies. These have shown instead either a defect in fetal catecholamine production [66] or a defect in lung maturation involving surfactant deficiency in the subset of Hif2a−/− offspring that survived to term [67]. The variability in phenotype may be related to differences in genetic background. Overall, the results suggest that despite similar activity on HRE-linked reporter genes, HIF-1␣ and HIF-2␣ have important non-redundant functions in the regulation of gene expression during development. In contrast to the role of HIF-1␣ and HIF-2␣ in mediating transcriptional activation, HIF-3␣ appears to be involved in negative regulation of the angiogenic response, through an alternately spliced transcript termed inhibitory PAS domain protein (IPAS), which has been shown to be expressed in the mouse cornea and mediate anti-angiogenic effects that may provide a mechanism for this tissue to remain avascular [21].

4. Therapeutic implications of HIF-1-regulated angiogenesis 4.1. 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 atherosclerotic cardiovascular disease the administration of a single angiogenic factor may be insufficient to induce angiogenesis, which involves the expression of multiple factors in a precise temporal and spatial pattern. HIF-1 regulates, either directly or indirectly, the cell type-specific expression of multiple angiogenic growth factors and cytokines, including angiopoietins, VEGF, PLGF, PDGF-B, and stromal-derived growth factor 1 (SDF-1) (Table 1 and [64]), suggesting that strategies

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designed to increase HIF-1 activity may be more efficacious than those which increase only a single factor. Experimental data in support of this hypothesis have been obtained, as described below. Several strategies have been used successfully for experimental activation of HIF-1. Deletion of the central O2 dependent degradation domain results in a stable and constitutively active HIF-1␣ molecule [26,64,70]. Transgenic expression of such a molecule in skin using a keratin 14 gene (K14) promoter results in marked activation of HIF-1 transcriptional targets and overgrowth of blood vessels [71]. Unlike mice that expressed a K14-VEGF transgene, the abundant cutaneous vessels were not leaky and the enhanced skin vascularity was not associated with edema. Another strategy has involved expression of a fusion protein consisting of the DNA-binding and dimerization domains of HIF-1␣ fused to the transactivation domain of herpes simplex virus VP16 [72]. In a rabbit hindlimb ischemia model, administration of plasmid DNA encoding the fusion protein resulted in improved recovery of blood flow, determined both in terms of the number of blood vessels and regional blood supply. Similar results have recently been reported in a rat myocardial infarction model [73]. An alternative adenoviral approach that did not involve the expression of a foreign protein was the use of AdCA5, a replication-defective recombinant adenovirus encoding a form of HIF-1␣ that was constitutively active due to the presence of deletion and point mutations that block O2 -dependent degradation of the protein [64]. Intravitreous injection of AdCA5 stimulated neovascularization of retinal vessels that do not respond to VEGF alone, an effect that was due to its ability to activate the expression of both PLGF and VEGF, which act synergistically in stimulating retinal neovascularization [64]. Intramuscular injection of AdCA5 promoted both angiogenic and arteriogenenic responses in a novel model of limb ischemia due to intravascular occlusion in rabbits that resembles atherosclerotic obstruction of peripheral arteries in patients [74]. AdCA5 injection increased capillary density as well as the luminal area of arteries. Increased expression of the genes encoding multiple angiogenic factors, including macrophage chemotactic protein 1 (MCP-1), PDGF-B, PLGF, SDF-1, and VEGF, provided a molecular basis for the observed stimulation of angiogenesis and arteriogenesis by AdCA5 [74]. An alternative to expressing a degradation-resistant form of HIF-1␣ is to administer a protein that inhibits the degradation of endogenous HIF-1␣. PR39, a macrophage-derived peptide, which was found to interact with the proteasome and selectively stabilize HIF-1␣, has been shown to increase peri-infarct vascularization in cardiac tissue of transgenic mice [75]. Administration of the prolyl hydroxylase inhibitor dimethyloxalylglycine has also been shown to increase VEGF production and capillary density in a mouse model of hindlimb ischemia [76]. Taken together, these studies suggest that activation of HIF-1 shows promise as a therapeutic intervention for treatment of ischemic cardiovascular disease.

However, it should be noted that preclinical studies of angiogenic growth factors also gave dramatic results and that thus far no clinical trials of any HIF-1-targeted therapy have been reported. In addition to the preclinical data from animal models, a recent clinical study has provided evidence that genetic variation at the HIF1A locus encoding HIF-1␣ may contribute to variation in the arteriogenic response to ischemia. About one-third of patients with ischemic heart disease due to atherosclerotic stenosis of one or more coronary arteries fail to develop collaterals in response to myocardial ischemia. Analysis of a genetic polymorphism that results in the substitution of serine for proline at residue 582 in HIF-1␣ revealed that the relative risk for absence of collaterals was increased five-fold in patients with the variant allele [77]. In these patients, a relative deficiency of HIF-1␣ may prevent the arteriogenic response and thus provide a rational basis for HIF-1␣ gene therapy. 4.2. Cancer HIF-1␣ overexpression is associated with increased microvessel density and/or VEGF expression in astrocytoma, gastrointestinal stromal cell tumor, bladder, malignant melanoma, oligodendroglioma, Wilms tumor, and colon, esophageal, endometrial, hepatocellular, non-small cell lung, ovarian, and pancreatic cancers (Table 4). HIF-1␣ expression levels are correlated with an increased risk of mortality in several types of carcinoma (Table 4). HIF-1 loss-of-function has Table 4 Association of HIF-1␣ with tumor vascularization and patient mortality Tumor type

Association

References

Astrocytoma, diffuse Bladder, superficial urothelial Bladder, transitional cell Breast Breast, c-erbB-2-positive Breast, LN-positive Breast, LN-negative Cervix, early-stage Cervix, RTX Cervix, IB-IIIB, RTX Colon Esophagus Esophagus Endometrial GIST, stomach Lung, NSCLC Malignant melanoma Oligodendroglioma Oropharynx-SCC Ovarian Pancreas Pancreas Wilms

Mortality, MVD Mortality (w/mut p53), MVD

[156] [157]

Mortality, grade, MVD, VEGF VEGF, DCIS MVD Mortality Mortality Mortality Mortality Mortality Mortality MVD, VEGF MVD, VEGF VEGF Mortality, VEGF, MVD Mortality, MVD, VEGF VEGF VEGF, mortality (HIF-2␣) Mortality, MVD Radiation resistance, mortality MVD, mortality (w/mut p53) MVD MVD, VEGF, metastasis VEGF

[158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178]

MVD: microvessel density; DCIS: ductal carcinoma in situ; SCC: squamous cell carcinoma; RTX: radiation therapy; GIST: gastrointestinal stromal tumor; NSCLC: non-small-cell lung carcinoma.

K. Hirota, G.L. Semenza / Critical Reviews in Oncology/Hematology 59 (2006) 15–26

been shown to inhibit tumor xenograft growth and angiogenesis in nude mice [78], whereas HIF-1 gain-of-function has the opposite effect [79]. Because of its important role in tumor vascularization, HIF-1 is now a target for cancer therapy [56]. Although interventions using dominant negative form of mutants of HIF-1␣, RNAi technology or decoy oligonucleotides against HIF-1␣ are under development, small molecule inhibitors of HIF-1 activity are of particular interest. The camptothecins, wellknown topoisomerase I inhibitors, inhibit HIF-1␣ protein accumulation [80,81]. A phase I clinical trial of topotecan, an FDA-approved semi-synthetic camptothecin analogue, given over an extended time course, is currently open for patient enrollment. A second drug already in clinical trials that inhibits HIF-1␣ protein accumulation is 2-methoxyestradiol [82]. Other HIF-1 inhibitors likely to enter the clinic soon are PX-478 and YC-1, which have shown impressive activity in tumor xenograft models [83,84]. For topotecan, 2methoxyestradiol, PX-478, and YC-1 the precise mechanisms of action are not known and the drugs target other proteins in addition to HIF-1. Chetomin, a dithiodiketopiperazine metabolite of the fungus Chaetomium species, inhibits HIF-1 transcriptional activity by binding to the coactivator p300 and blocking its interaction with HIF-1␣ and HIF-2␣ [85]. Other anticancer agents, such as rapamycin and the heat shock protein 90 inhibitor 17-AAG, also inhibit HIF-1 activity [86,87]. As in the case of every other protein implicated in cancer pathogenesis, HIF-1␣ overexpression does not occur in every cancer and when it does occur it is not always associated with increased mortality [56]. This evidence suggests that HIF-1 will not be a therapeutic target in all cancers. The relative contributions of HIF-1␣ and HIF-2␣ in different cancers may also vary. For example, in experimental models of clear-cell renal carcinoma both gain-of-function and loss-of-function studies have shown that HIF-2␣ rather than HIF-1␣ plays a critical role in the growth of tumor xenografts [88,89].

5. Conclusion The regulation of angiogenesis and arteriogenesis by HIF1 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 have a useful therapeutic window remains to be established. Agents that promote angiogenesis may be beneficial in cardiovascular disease but cause undesirable side effects if the patient is harboring an occult carcinoma. Similarly, agents that inhibit angiogenesis may have anti-cancer effects but may also worsen ischemic cardiovascular disease. Thus, much work remains to be done

21

to discover optimal therapeutic agents and to identify appropriate patient populations in which their administration will result in an improved clinical outcome.

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, Cleveland, OH 44106-4970, USA.

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.).

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Biographies 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.