Biomol Ther (Seoul) 2014; 22(1): 1-9  https://doi.org/10.4062/biomolther.2013.113
VEGF-VEGFR Signals in Health and Disease
Masabumi Shibuya1,2,3,*

1Jobu University, Director, Institute of Physiology and Medicine, Gunma 372-8588

2Tokyo Medical and Dental University, Department of Molecular Oncology, Tokyo 113-8519

3University of Tokyo, Tokyo 108-8639, Japan

*Corresponding Author: E-mail: shibuya@ims.u-tokyo.ac.jp, Tel: +81-270-32-1010, Fax: +81-270-32-1021(Jobu University)
Received: December 30, 2013; Accepted: January 15, 2014; Published online: January 30, 2014.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.

Keywords: VEGF, VEGF receptor, Angiogenic signals, Anti-Angiogenic therapy
INTRODUCTION

Vertebrates, including humans, have a closed circulatory system for supplying oxygen and nutrients to various tissues in the body, and for removing CO2 and waste materials from peripheral tissues (Risau, 1997). In addition to the blood circulatory system, vertebrates have a similar tubular system, the lymph vessel system, which is essential for the absorption and delivery of fluids, lipids and immune cells from peripheral tissues to lymph nodes and circulating blood.

The circulatory system plays a crucial role in the etiology of many diseases in humans. The hypothesis that suppressing tumor angiogenesis was a potentially novel anti-cancer strategy was first suggested by J. Folkman in 1970 (for review, Hanahan and Folkman, 1996), although the molecular basis of the regulation of angiogenesis was not clearly characterized prior the late 1980s.

Around 1990th, the genes encoding vascular endothelial growth factor (VEGF) and its receptor (VEGFR) were isolated and characterized. Based on extensive studies of these molecules, signals mediated by members of the VEGF and VEGFR families were shown to play central roles in angiogenesis and lymphangiogenesis (Leung et al., 1989; Shibuya et al., 1990; Alitalo and Carmeliet, 2002; Ferrara, 2004; Shibuya and Claesson-Welsh, 2006; Shibuya, 2011).

In parallel to the VEGF-VEGFR axis, other regulatory systems, including angiopoietin (Ang)-Tie, Delta-Notch and Ephrin-Eph, have been shown to play a role in angiogenesis (Suri et al., 1996; Wang et al., 1998; Noguera-Troise et al., 2006). Furthermore, studies have demonstrated the existence of a variety of endogenous anti-angiogenic factors, such as thrombospondin-1 (TSP-1), as well as factors involved in negative feedback loops that act to suppress angiogenesis (Watnick et al., 2003).

Based on the knowledge that VEGF signals are key players in tumor angiogenesis, a variety of antibodies and kinase inhibitors which suppress VEGF-VEGFR signaling have been developed that are now widely used in the treatment of cancer. The clinical efficacy of such therapeutics is limited however, and many future studies will focus on improving their performance in the clinic (Hurwitz et al., 2004).

Recently, a soluble form of Flt-1/VEGFR-1, sFlt-1, has been shown to be associated with preeclampsia (PE) (Maynard et al., 2003; Koga et al., 2003; Levine et al., 2004; Young et al., 2010), aged macular degeneration (AMD) (Luo et al., 2013) and nephrotic syndrome (Jin et al., 2012). Furthermore, VEGF signals have been reported to directly regulate neuronal function and survival under certain conditions (Oosthuyse et al., 2001). These results are discussed in this review.

STRUCTURAL AND BIOLOGICAL CHARACTERISTICS OF VEGFS

In 1989, two research groups independently isolated a cDNA, one encoding for vascular permeability factor (VPF) and another for VEGF, which proved to be identical, and encoded a single protein, now widely known as VEGF (for review, Dvorak, 2002; Ferrara, 2004). The human genome contains five genes encoding five distinct VEGF family members, namely VEGFA (also called VEGF), placenta growth factor (PlGF), VEGFB, VEGF-C, and VEGF-D (Fig. 1). Structurally, VEGF family proteins are homodimeric, with two subunits of about 120 to 200 amino acids in length. Given their overall structural resemblance to members of the platelet-derived growth factor (PDGF)/macrophage colony-stimulating factor (M-CSF)/stem cell factor (SCF) ligand family, the VEGF and PDGF families are considered to constitute a supergene family, the VEGFPDGF superfamily. With regard to interactions between VEGF ligands and their receptors, VEGF-A, which contains subtypes such as VEGF-121, -165 and -189, binds VEGFR-1/Flt-1 and VEGFR-2 (De Vries et al., 1992), whereas PlGF and VEGF-B bind only VEGFR-1/Flt-1. VEGF-C and VEGF-D bind tightly to VEGFR-3 and more weakly to VEGFR-2. Interestingly, a possibly suppressive ligand, VEGF(xxx)b, has recently been reported (Pritchard-Jones et al., 2007). Although it does not exist in mammalian genome, another VEGF family member, VEGFE encoded in the Orf-viral genome, has been shown to be a VEGFR-2 specific ligand (Shibuya and Claesson-Welsh, 2006).

VEGF-A (+/−) mice, in which a single allele of VEGF-A has been deleted, exhibit embryonic lethality due to immature angiogenesis and cardiovascular insufficiency. Lethality resulting from loss of a single allele of a gene is rare in mammals, and the phenotype of these mice indicates a strict relationship between VEGF dosage and angiogenic homeostasis (Carmellet et al., 1996; Ferrara et al., 1996). Expression of VEGF-A is known to be upregulated under hypoxic conditions, as well as by growth factor signaling, and by hormones such as estrogen (Ferrara, 2004).

In contrast to VEGF-A, PlGF and VEGF-B appear to have a relatively minor role in the regulation of angiogenesis, and have been shown to play a role in cardiac muscle function (Bellomo et al., 2000; Bry et al., 2010). VEGF-C and VEGF-D are initially synthesized as precursor forms that subsequently undergo post-translational processing, and are involved in the regulation of lymphangiogenesis (Alitalo and Carmeliet, 2002). Moreover, they have been demonstrated to be involved in angiogenesis at early stage of embryogenesis, approximately E10.5, as well as in tumor angiogenesis (Dumont et al., 1998; Tammela et al., 2008).

UNIQUE STRUCTURE AND SIGNALING OF VEGFRS

In 1990, our group isolated a cDNA from human placenta that encoded a novel receptor-type tyrosine kinase containing seven extracellular immunoglobulin (Ig)-domains and a kinase insert sequence of approximately 70 amino acids in length. Based on its structural similarity to the Fms receptor, we named it Fms-like tyrosine kinase-1 (Flt-1) (Shibuya et al., 1990). In addition to full length Flt-1, we found that human placenta also expressed a truncated mRNA encoding a protein named sFlt-1, which contained only the ligand-binding region of Flt-1 (Shibuya et al., 1990; Kendall and Thomas, 1993) (Fig. 1). Based on a subsequent study demonstrating its high affinity for VEGF (De Vries et al., 1992), Flt-1 is also referred to as VEGFR-1. Soon after the isolation of Flt-1, VEGFR-2/KDR (Flk-1 in mouse) and VEGFR-3/Flt-4 were isolated, indicating the existence of three distinct VEGFR genes in the mammalian genome.

VEGF-A binds to VEGFR-1/Flt-1 with high affinity (Kd=1–10 pM) and less strongly to VEGFR-2 (Kd=10–100 pM), although the tyrosine kinase (TK) activity of VEGFR-1/Flt-1 is about 10 fold weaker than VEGFR-2 (Keyt et al., 1996; Sawano et al., 1996). Along with the results of gene knockout studies, these data indicate that the major signal transducer in angiogenesis is VEGFR-2 (Shalaby et al., 1995). The VEGF-VEGFR-2 axis regulates angiogenesis in a number of different physiological contexts, including hormone-dependent angiogenesis (Ferrara, 2004; Kim et al., 2013).

Members of the PDGFR/Fms (M-CSF receptor)/Kit family are distantly related to VEGFRs, and are known to signal through PI3K activation domains with tyrosine (Y)-containing motifs such as Y-x-x-methionine (M) and Y-M-x-M, at the TK-insert domain. After autophosphorylation of PDGFR family members, the p85 subunit of PI3K binds the Y-x-x-M and YM-x-M motifs via SH2 domain, resulting in activation of downstream PI3K-Akt and Ras pathways and strong signaling for cell proliferation (Heldin and Westermark, 1999). Very interestingly however, VEGFRs, including VEGFR-2, lack Y-M-x-M and Y-x-x-M motifs in the TK-insert and other regions. In contrast, we found that VEGFR-2 Y1175, a major autophosphorylation site of this receptor, binds the SH2 domain of PLCγ, activating the PLCγ-C kinase-Raf-MEK-MAP kinase pathway to mediate endothelial cell proliferation (Takahashi et al., 1999; Takahashi et al., 2001). Similar to flk-1 (VEGFR-2)−/− mice, VEGFR-2 Y1173F homozygous knock-in mice, in which this tyrosine residue is mutated to phenylalanine (F) (the mouse VEGFR2 protein is two amino acid shorter than the human form), exhibit embryonic lethality due to poor vasculogenesis and angiogenesis (Sakurai et al., 2005). Furthermore, Sase et al. (2009) reported that, using an in vitro ES cell differentiation system into vascular endothelial cells, Y1175F-mutant VEGFR-2 fails to induce endothelial differentiation. Collectively, these reports indicate that VEGF-VEGFR-2 mediated signal for vasculogenesis and angiogenesis is highly dependent on the Phospho (P)Y1175-PLCγ-C kinase pathway.

VEGFR-2 Y1175 has also been shown to be involved in von Willebrand factor release from endothelial cells (Xiong et al., 2009), while VEGFR-2 Y951 is important for vascular permeability and cell migration (Matsumoto et al., 2005). In addition, the VEGFR-2-Hdac6-Hsp90-Bcl2 pathway has been reported to transduce cell survival signals (Dias et al., 2002).

While most TK family kinases engage the Ras activation pathway to stimulate cell proliferation, this pathway appears to be relatively unimportant in VEGFR-2 signaling. The dependence of VEGFR-2 on PLCγ-C kinase in signaling for the MAP kinase activation is therefore unique among TK family members.

VEGFR-1/FLT-1 AND VEGFR-3

The biological characteristics of VEGFR-1/Flt-1 are distinct from those of VEGFR-2. Fong et al. (1995) reported that flt-1 −/− mice are embryonic lethal due to overgrowth of endothelial cells and dysfunction of blood vessels. These results strongly suggest that VEGFR-1/Flt-1 has a negative role in angiogenesis at an early stage of embryogenesis, possibly by maintaining an appropriate level of activation of VEGFR-2 via partial suppression of VEGF. To clarify whether the VEGF-trapping with the binding domain of VEGFR-1/Flt-1 or the TK-dependent negative signaling is crucial for this biological role of VEGFR-1/Flt-1 in embryogenesis, we generated Flt-1 TK-deficient (flt-1 TK−/−) mice. To our surprise, flt-1 TK−/− mice were viable and showed basically normal blood vessel formation (Hiratsuka et al., 1998). These mice, however, exhibited a deficiency in VEGF-dependent migration of macrophages which is in agreement with expression of VEGFR-1/Flt-1 in macrophages and its role in VEGF-dependent macrophage migration (Barleon et al., 1996; Clauss et al., 1996).

Since the flt-1 TK−/− mice lack only signals mediated by VEGFR-1/Flt-1, they are useful for elucidating the importance of VEGFR-1 signals under physiological conditions (Niida et al., 2005), as well as in diseases such as cancer. Studies using these mice by our own group and others have demonstrated that VEGFR-1 TK stimulates angiogenesis in various carcinomas and glioblastomas (Kerber et al., 2008; Muramatsu et al., 2010; Schwartz et al., 2010; Laurent et al., 2011), tumor metastasis (Hiratsuka et al., 2002; Kaplan et al., 2005), inflammatory disease similar to rheumatoid arthritis (Murakami et al., 2006), stroke (Beck et al., 2010), as well as liver repair (Kato et al., 2011) and gastric ulcer healing (Sato et al., 2013). These results indicate that although its TK activity itself is 10-fold weaker than that of VEGFR-2, VEGFR-1/Flt-1 nonetheless represents a potentially important therapeutic target in a variety of diseases, particularly cancer (Shibuya, 2006).

VEGFR-3 is highly expressed in lymphatic endothelial cells, and VEGF-C/D-VEGFR-3 signals have been shown to stimulate lymphangiogenesis and lymph-node metastasis in cancer. In addition, VEGFR-3 has been shown to play a role in tumor angiogenesis (Tammela et al., 2008; Sallinen et al., 2011).

ANGIOGENESIS-REGULATORY SYSTEMS OTHER THAN VEGFS, AND ENDOGENOUS ANTI-ANGIOGENIC MOLECULES

Recently a variety of angiogenesis-regulatory systems have been elucidated, including: the Ang-Tie receptor axis, which mediates stabilization or destabilization of blood vessels; the Ephrin-Eph receptor pathway, which plays a role in arterio-venous differentiation of vessels; the Delta-Notch pathway, which is involved in regulation of vascular morphology and tip cell-stalk cell communication; and the Netrins-UNC5R pathway, which plays a role in guidance during angiogenesis (Suri et al., 1996; Wang et al., 1998; Noguera-Troise et al., 2006; Freitas et al., 2008). Of these, the Delta-Notch receptor system, particularly that involving Dll4, has attracted attention given its crucial role in sprouting and morphogenesis during angiogenesis. Anti-Dll4 neutralizing antibodies were shown to suppress tumor growth in mice, initially suggesting that this might represent an alternative strategy for blocking tumor angiogenesis (Noguera-Troise et al., 2006). However, although Dll4 blockade using these antibodies suppressed tubular formation by endothelial cells, these endothelial cells survived in tissues and gave rise to angiomas (Yan et al., 2010). This finding resulted in the termination or significant suppression of development of anti-tumor drugs based on Dll4 blockade.

In addition to these angiogenesis-regulatory systems, a variety of endogenous angio-suppressive factors have been identified. TSP-1, for example, has been shown to suppress angiogenesis by inducing apoptosis or cell cycle arrest of vascular endothelial cells via upregulation of p21 (Watnick et al., 2003; Yamauchi et al., 2007). Down syndrome patients show lower incidence of cancer. A gene DSCR-1 responsible for anti-cancer was recently identified (Minami et al., 2004). DSCR-1 protein has an anti-angiogenic activity, and an increase in the gene copy number of DSCR-1 gene in Down syndrome patients appear to partly suppress tumor angiogenesis. In addition, VASH1, which is induced in endothelial cells subsequent to activation of VEGF-VEGFR, have been shown to possess anti-angiogenic activity (Sato, 2013). Moreover, angiostatin and endostatin have been characterized as endogenous tumor suppressors in animal models, although it is not clear whether they possess similar roles in humans.

Future studies will be required to clarify which of these factors and signaling pathways are involved in suppressing tumor angiogenesis and which, if any, are suitable for development of therapeutics for clinical use.

VEGF-VEGFR INHIBITORS: DEVELOPMENT OF ANTI-ANGIOGENIC THERAPY

Based on the evidence that VEGF-VEGFR signals play central roles in angiogenic processes in a variety of diseases such as cancer, various VEGF signal inhibitors, including anti-VEGF neutralizing antibodies and VEGFR kinase/multi kinase inhibitors, have been successfully developed and now widely used in the clinic (Kim et al., 1993; Hurwitz et al., 2004) (Fig. 2, 3). These drugs are effective in prolongation of PFS (progression-free survival) as well as OS (overall survival) in the treatment of cancer, and have been approved for a variety of solid tumors such as colorectal cancer, lung cancer (nonepithelial, NSCLC), breast cancer, glioblastoma, liver cancer and renal cell carcinoma (Hurwitz et al., 2004; Cohen et al., 2007). The efficacy of anti-VEGF antibody in breast cancer is complex however, in that unlike previous relatively small size phase III studies, recent large scale phase III studies have indicated that a combination of chemotherapy plus anti-VEGF antibody treatment was better than chemotherapy-only treatment with respect to PFS, but not OS. Based on this result, the United States Food and Drug Administration withdrew its approval for the use of anti-VEGF antibody in breast cancer treatment. In contrast however, citing its improvement of PFS in patients, Japan and other countries approved anti-VEGF antibodies for the treatment of breast cancer in 2011. More recently an anti-VEGF antibody has been approved for the treatment of ovarian cancer based on the successful clinical trials.

Given the potential of adverse clinical effects of small molecules kinase inhibitors, novel compounds are currently undergoing clinical trials to identify drugs with fewer side effects.

To date, there have been no successful results in the use of anti-VEGF signaling drugs in the treatment of pancreatic or gastric cancer.

While the clinical efficacy of anti-VEGFs has been demonstrated in solid tumors, it is not clear whether this benefit continues for long periods. OS curves in some phase III trials indicate that over time their efficacy decreases, and the potential for resistance or refractoriness exists in later periods. Refractoriness may be due to several possible mechanisms as follows: (1) other angiogenic factors such as HGF and FGF compensate for the loss of the VEGF proangigenic signal (Pàez-Ribes et al., 2009), (2) vascular endothelial cells in tumor tissue acquire increased resistance to anti VEGF-VEGFR drugs (Hida et al., 2013), or (3) in response to the conditions of hypoxia and low nutrition which result from anti-angiogenic therapy, cancer cells may become more invasive and/or resistant to apoptosis by induction of phospho-Akt and upregulation of histone-demetylases such as JHJM1A (Huveldt et al., 2013; Osawa et al., 2013) (Fig. 4). Extensive studies are required to elucidate the actual mechanism of resistance in this context.

Anti-VEGF signal inhibitors have been shown to be effective in suppressing symptoms of AMD. A recovery of visual acuity was demonstrated in response to intraocular injection of an anti-VEGF neutralizing antibody.

NEW INFORMATION ON AN INTIMATE RELATIONSHIP BETWEEN VEGF SIGNALING AND DISEASES OTHER THAN CANCER

PE, which occurs in 5–7% of pregnancies, causes hypertension and proteinuria in the mother and growth retardation in the fetus, and Cesarean section is often required to save the fetus. sFlt-1 is present at high levels in the serum of PE patients, and the degree of sFlt-1 overexpression has been shown to correlate with the severity of PE (Koga et al., 2003; Maynard et al., 2003) (Fig. 1). Furthermore, Levine et al. (2004) found that elevated sFlt-1 in the serum in asymptomatic women at early stages of pregnancy predisposed to the development of PE in the later stages of pregnancy. In animal models, inoculation of sFlt-1 expression vector into pregnant rats induced hypertension and proteinuria, similar to PE in humans (Maynard et al., 2003).

Since sFlt-1 is derived from the ligand-binding region of VEGFR-1/Flt-1, its major biochemical function is thought to be trapping of VEGF for suppression of VEGF signals (Tanaka et al., 1997; Shibuya, 2006). To our surprise, cancer patients treated with anti-VEGF signal drugs often develop side effects such as hypertension and proteinurea that are similar to the symptoms of PE (Hurwitz et al., 2004). Taken together, these results indicate that the abnormally high levels of sFlt-1 secreted from trophoblasts in placenta contribute to the development of PE, and that strategies targeting this protein have considerable potential in the treatment of this disease (Mezquita et al., 2003; Nagamatsu et al., 2004; Gilbert et al., 2007; Foidart et al., 2009; Kumasawa et al., 2011; Thadhani et al., 2011).

Furthermore, sFlt-1 is expressed in lens epithelial cells as well as pigment epithelial and photoreceptor cells in the eye, where it plays a role in maintaining avascularity in the cornea and in tissues outside of the retina (Ambati et al., 2006; Luo et al., 2013) (Fig. 5). Decreased expression of sFlt-1 in photo-receptor and pigment epithelial cells has been reported in AMD patients, suggesting that an increase in free VEGF may stimulate pathological angiogenesis in the retinas of these individuals.

sFlt-1 is also expressed in podocytes in the kidney, where it binds to the cell membrane lipid to maintain the physiological functions of podocytes and vascular endothelial cells in renal glomeruli (Jin et al., 2012). Interestingly, sFlt-1 does not necessarily sequester VEGF in podocytes, and sFlt-1 localized in lipid rafts in the cell surface of podocytes is sufficient to support physiological secretion of primary urine from glomerular capillaries. Indeed, podocyte-specific knock-out of the flt-1 gene in mice has been shown to induce chronic proteinuria, a condition characteristic of nephrotic syndrome in humans (Jin et al., 2012).

Another exciting advance in the VEGF-VEGFR field in past 12 years is the discovery of an intimate relationship between VEGF signaling and the neuronal system. Although VEGF signaling in neuronal tissues was thought to function directly upon blood vessels rather than neuronal cells, an extensive study clearly showed that this is not the case (Oosthuyse et al., 2001). A hypoxia response element (HRE) sequence in the transcriptional regulatory region of VEGF gene mediates hypoxia-inducible factor (HIF) binding, and is essential for hypoxia-responsive upregulation of VEGF. Deletion of this HRE sequence in mice (VEGFδ/δ mice) resulted in motor neuron degeneration several months after birth, whose pathological alterations in neurons are comparable to amyotrophic lateral sclerosis (ALS) in humans. They also showed that although decreased angiogenesis due to reduced VEGF levels contributes to this phenomenon in part, a direct effect of VEGF on motor neuron also appears to be important. In vitro studies have shown that purified motor neurons express VEGFR-2, and that VEGF signals via VEGFR-2 to stimulate cell survival. Furthermore, treatment of VEGFδ/δ mice with VEGF results in partial suppression of their motor neuron degeneration, strongly suggesting that stimulation of VEGF signaling is an attractive new strategy for the treatment of ALS patients.

Sensory nerve cells in the dorsal root ganglion of mice also express VEGFR-2, and VEGF signals are required to maintain the healthy condition of these cells (Verheyen et al., 2012). Blockade of this signal by drugs such as anti-VEGF neutralizing antibodies results in painful sensory neuropathy, an adverse effect of anti-VEGF signaling therapy. Further studies on this problem are required to improve PFS in cancer patients undergoing anti-VEGF therapy.

On the other hand, olfactory sensory neurons express VEGFR-1, and the VEGF-VEGFR-1 pathway has been shown to be important for physiological function of these neurons (Wittko et al., 2009; Dhondt et al., 2011). Various neuronal diseases should be carefully characterized in the VEGF signal point of view.

CONCLUSION

VEGF signaling plays a crucial role not only in cancer but also in a variety of other diseases, including neuronal degeneration and nephrotic syndrome. We anticipate that further studies on VEGF signaling and its modulators will herald a new era in which the severe diseases whose etiology is associated with abnormal VEGF signaling can be brought under control.

Figures
Fig. 1. VEGF-VEGFR system: a crucial regulator of angiogenesis and lymphangiogenesis. Genes encoding all VEGF family members except VEGF-E are present in the mammalian genome. Abnormally high or low expression of sFlt-1 correlates with a variety of diseases.
Fig. 2. A summary of the clinical use of anti-angiogenic therapy. Anti VEGF neutralizing antibodies (Bevacizumab, Ranibizumab), VEGF165-neutralizing RNA aptamer (Pegaptanib), VEGFR1-R2 fusion peptide (VEGF-A-Trap) and VEGFR/multi TK inhibitors (Sorafenib, Sunitinib, etc.) were approved for clinical use. Bevacizumab and VEGFR/multi TK inhibitors are for the treatment of cancer. Others are for the treatment of AMD.
Fig. 3. Hypothetical response of tumors to anti-angiogenic therapy. The double stresses of hypoxia and low nutrition in tumor cells after anti-angiogenic therapy, might result in the acquisition of resistance to drugs.
Fig. 4. Anti-tumor angiogenesis therapy: is targeting VEGF signals effective in later stages of cancer? The clinical efficacy of anti VEGF signal drugs may decrease in later stages of cancer, prompting the search for novel anti-angiogenic drugs.
Fig. 5. sFlt-1 (soluble VEGF receptor-1) is important for the maintenance of the photoreceptor avascular area in the eye. AMD (aged macular degeneration) is characterized by a decrease in sFlt-1 levels, resulting in increased in VEGF levels and inappropriate angiogenesis (Luo et al., 2013).
References
  1. Alitalo, K, Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell, 2002;1;219-227.
    Pubmed
  2. Ambati, BK, Nozaki, M, Singh, N, Takeda, A, Jani, PD, Suthar, T, Albuquerque, RJ, Richter, E, Sakurai, E, Newcomb, MT, Kleinman, ME, Caldwell, RB, Lin, Q, Ogura, Y, Orecchia, A, Samuelson, DA, Agnew, DW, St Leger, J, Green, WR, Mahasreshti, PJ, Curiel, DT, Kwan, D, Marsh, H, Ikeda, S, Leiper, LJ, Collinson, JM, Bogdanovich, S, Khurana, TS, Shibuya, M, Baldwin, ME, Ferrara, N, Gerber, HP, De Falco, S, Witta, J, Baffi, JZ, Raisler, BJ, Ambati, J. Corneal avascularity is due to soluble VEGF receptor-1. Nature, 2006;443;993-997.
    Pubmed
  3. Barleon, B, Sozzani, S, Zhou, D, Weich, HA, Martovani, A, Marme, D. Migration of human monocytes in response to vascular endothelilal growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood, 1996;87;3336-3343.
    Pubmed
  4. Beck, H, Raab, S, Copanaki, E, Heil, M, Scholz, A, Shibuya, M, Deller, T, Machein, M, Plate, KH. VEGFR-1 signaling regulates the homing of bone marrow derived cells in a mouse stroke model. J Neuropathol Exp Neurol, 2010;69;168-175.
    Pubmed
  5. Bellomo, D, Headrick, JP, Silins, GU, Paterson, CA, Thomas, PS, Gartside, M, Mould, A, Cahill, MM, Tonks, ID, Grimmond, SM, Townson, S, Wells, C, Little, M, Cummings, MC, Hayward, NK, Kay, GF. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res, 2000;86;E29-35.
    Pubmed
  6. Bry, M, Kivel?, R, Holopainen, T, Anisimov, A, Tammela, T, Soronen, J, Silvola, J, Saraste, A, Jeltsch, M, Korpisalo, P, Carmeliet, P, Lemstr?m, KB, Shibuya, M, Yl?-Herttuala, S, Alhonen, L, Mervaala, E, Andersson, LC, Knuuti, J, Alitalo, K. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation, 2010;122;1725-1733.
    Pubmed
  7. Carmellet, P, Ferreira, V, Breier, G, Pollefeyt, S, Kleckens, L, Gertsenstein, M, Fahrig, M, Vandenhoeck, A, Harpal, K, Eberhardt, C, Declercq, C, Pawlling, J, Moons, L, Collen, D, Risau, W, Nagy, A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 1996;380;435-439.
    Pubmed
  8. Clauss, M, Weich, H, Breier, G, Knies, U, R?ckl, W, Waltenberger, J, Risau, W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. J Biol Chem, 1996;271;17629-17634.
    Pubmed
  9. Cohen, MH, Gootenberg, J, Keegan, P, Pazdur, R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist, 2007;12;713-718.
    Pubmed
  10. De Vries, C, Escobedo, JA, Ueno, H, Houck, K, Ferrara, N, Williams, LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science, 1992;255;989-991.
    Pubmed
  11. Dhondt, J, Peeraer, E, Verheyen, A, Nuydens, R, Buysschaert, I, Poesen, K, Van Geyte, K, Beerens, M, Shibuya, M, Haigh, JJ, Meert, T, Carmeliet, P, Lambrechts, D. Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB J, 2011;25;1461-1473.
    Pubmed
  12. Dias, S, Shmelkov, SV, Lam, G, Rafii, S. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood, 2002;99;2532-2540.
    Pubmed
  13. Dumont, DJ, Jussila, L, Taipale, J, Lymboussaki, A, Mustonen, T, Pajusola, K, Breitman, M, Alitalo, K. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science, 1998;282;946-949.
    Pubmed
  14. Dvorak, HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol, 2002;20;4368-4380.
    Pubmed
  15. Ferrara, N, Carver-Moore, K, Chen, H, Dowd, M, Lu, L, O’Shea, KS, Powell-Braxton, L, Hillan, KJ, Moore, MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature, 1996;380;439-442.
    Pubmed
  16. Ferrara, N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev, 2004;25;581-611.
    Pubmed
  17. Foidart, JM, Schaaps, JP, Chantraine, F, Munaut, C, Lorquet, S. Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia-a step forward but not the definitive answer. J Reprod Immunol, 2009;82;106-111.
    Pubmed
  18. Fong, GH, Rossant, J, Gertsentein, M, Breitman, ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature, 1995;376;66-70.
    Pubmed
  19. Freitas, C, Larriv?e, B, Eichmann, A. Netrins and UNC5 receptors in angiogenesis. Angiogenesis, 2008;11;23-29.
    Pubmed
  20. Gilbert, JS, Babcock, SA, Granger, JP. Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble Fms-like tyrosine kinase-1 expression. Hypertension, 2007;50;1142-1147.
    Pubmed
  21. Hanahan, D, Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996;86;353-364.
    Pubmed
  22. Heldin, CH, Westermark, B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev, 1999;79;1283-1316.
    Pubmed
  23. Hida, K, Ohga, N, Akiyama, K, Maishi, N, Hida, Y. Heterogeneity of tumor endothelial cells. Cancer Sci, 12 Aug 2013[Epub ahead of print]
    CrossRef
  24. Hiratsuka, S, Minowa, O, Kuno, J, Noda, T, Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA, 1998;95;9349-9354.
    Pubmed
  25. Hiratsuka, S, Nakamura, K, Iwai, S, Murakami, M, Itoh, T, Kijima, H, Shipley, JM, Senior, RM, Shibuya, M. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung specific metastasis. Cancer Cell, 2002;2;289-300.
    Pubmed
  26. Hurwitz, H, Fehrenbacher, L, Novotny, W, Cartwright, T, Hainsworth, J, Heim, W, Berlin, J, Baron, A, Griffing, S, Holmgren, E, Ferrara, N, Fyfe, G, Rogers, B, Ross, R, Kabbinavar, F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for meta-static colorectal cancer. N Engl J Med, 2004;350;2335-2342.
    Pubmed
  27. Huveldt, D, Lewis-Tuffin, LJ, Carlson, BL, Schroeder, MA, Rodriguez, F, Giannini, C, Galanis, E, Sarkaria, JN, Anastasiadis, PZ. Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. PLoS One, 2013;8;e56505.
    Pubmed
  28. Jin, J, Sison, K, Li, C, Tian, R, Wnuk, M, Sung, HK, Jeansson, M, Zhang, C, Tucholska, M, Jones, N, Kerjaschki, D, Shibuya, M, Fantus, IG, Nagy, A, Gerber, HP, Ferrara, N, Pawson, T, Quaggin, SE. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell, 2012;151;384-399.
    Pubmed
  29. Kaplan, RN, Riba, RD, Zacharoulis, S, Bramley, AH, Vincent, L, Costa, C, MacDonald, DD, Jin, DK, Shido, K, Kerns, SA, Zhu, Z, Hicklin, D, Wu, Y, Port, JL, Altorki, N, Port, ER, Ruggero, D, Shmelkov, SV, Jensen, KK, Rafii, S, Lyden, D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 2005;438;820-827.
    Pubmed
  30. Kato, T, Ito, Y, Hosono, K, Suzsuki, T, Tamaki, H, Minamino, T, Kato, S, Sakagami, H, Shibuya, M, Majima, M. Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity. Toxicol Sci, 2011;120;218-229.
    Pubmed
  31. Kendall, RL, Thomas, KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA, 1993;90;10705-10709.
    Pubmed
  32. Kerber, M, Reiss, Y, Wickersheim, A, Jugold, M, Kiessling, F, Heil, M, Tchaikovski, V, Waltenberger, J, Shibuya, M, Plate, KH, Machein, MR. Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res, 2008;68;7342-7351.
    Pubmed
  33. Keyt, BA, Nguyen, HV, Berleau, LT, Duarte, CM, Park, J, Chen, H, Ferrara, N. Identification of vascular endothelial growth factor determinanats for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J Biol Chem, 1996;271;5638-5646.
    Pubmed
  34. Kim, KJ, Li, B, Winer, J, Armanini, M, Gillett, N, Phillips, HS, Ferrara, N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature, 1993;362;841-844.
    Pubmed
  35. Kim, M, Park, HJ, Seol, JW, Jang, JY, Cho, YS, Kim, KR, Choi, Y, Lydon, JP, Demayo, FJ, Shibuya, M, Ferrara, N, Sung, HK, Nagy, A, Alitalo, K, Koh, GY. VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodeling during pregnancy. EMBO Mol Med, 2013;5;1415-1430.
    Pubmed
  36. Koga, K, Osuga, Y, Yoshino, O, Hirota, Y, Ruimeng, X, Hirata, T, Takeda, S, Yano, T, Tsutsumi, O, Taketani, Y. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab, 2003;88;2348-2351.
    Pubmed
  37. Kumasawa, K, Ikawa, M, Kidoya, H, Hasuwa, H, Saito-Fujita, T, Morioka, Y, Takakura, N, Kimura, T, Okabe, M. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci USA, 2011;108;1451-1455.
    Pubmed
  38. Laurent, J, Hull, EF, Touvrey, C, Kuonen, F, Lan, Q, Lorusso, G, Doucey, MA, Ciarloni, L, Imaizumi, N, Alghisi, GC, Fagiani, E, Zaman, K, Stupp, R, Shibuya, M, Delaloye, JF, Christofori, G, Ruegg, C. Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. Cancer Res, 2011;71;3781-3791.
    Pubmed
  39. Leung, DW, Cachianes, G, Kuang, WJ, Goeddel, DV, Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989;246;1306-1309.
    Pubmed
  40. Levine, RJ, Maynard, SE, Qian, C, Lim, KH, England, LJ, Yu, KF, Schisterman, EF, Thadhani, R, Sachs, BP, Epstein, FH, Sibai, BM, Sukhatme, VP, Karumanchi, SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med, 2004;350;672-683.
    Pubmed
  41. Luo, L, Uehara, H, Zhang, X, Das, SK, Olsen, T, Holt, D, Simonis, JM, Jackman, K, Singh, N, Miya, TR, Huang, W, Ahmed, F, Bastos-Carvalho, A, Le, YZ, Mamalis, C, Chiodo, VA, Hauswirth, WW, Baffi, J, Lacal, PM, Orecchia, A, Ferrara, N, Gao, G, Young-Hee, K, Fu, Y, Owen, L, Albuquerque, R, Baehr, W, Thomas, K, Li, DY, Chalam, KV, Shibuya, M, Grisanti, S, Wilson, DJ, Ambati, J, Ambati, BK. Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1. Elife, 2013;2;e00324.
    Pubmed
  42. Matsumoto, T, Bohman, S, Dixelius, J, Berge, T, Dimberg, A, Magnusson, P, Wang, L, Wikner, C, Qi, JH, Wernstedt, C, Wu, J, Bruheim, S, Mugishima, H, Mukhopadhyay, D, Spurkland, A, Claesson-Welsh, L. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J, 2005;24;2342-2353.
    Pubmed
  43. Maynard, SE, Min, JY, Merchan, J, Lim, KH, Li, J, Mondal, S, Libermann, TA, Morgan, JP, Sellke, FW, Stillman, IE, Epstein, FH, Sukhatme, VP, Karumanchi, SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest, 2003;111;649-658.
    Pubmed
  44. Mezquita, J, Mezquita, B, Pau, M, Mezquita, C. Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262. J Cell Biochem, 2003;89;1138-1147.
    Pubmed
  45. Minami, T, Horiuchi, K, Miura, M, Abid, MR, Takabe, W, Noguchi, N, Kohro, T, Ge, X, Aburatani, H, Hamakubo, T, Kodama, T, Aird, WC. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem, 2004;279;50537-50554.
    Pubmed
  46. Murakami, M, Iwai, S, Hiratsuka, S, Yamauchi, M, Nakamura, K, Iwakura, Y, Shibuya, M. Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages. Blood, 2006;108;1849-1856.
    Pubmed
  47. Muramatsu, M, Yamamoto, S, Osawa, T, Shibuya, M. Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res, 2010;70;8211-8221.
    Pubmed
  48. Nagamatsu, T, Fujii, T, Kusumi, M, Zou, L, Yamashita, T, Osuga, Y, Momoeda, M, Kozuma, S, Taketani, Y. Cytotropho-blasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology, 2004;145;4838-4845.
    Pubmed
  49. Niida, S, Kondo, T, Hiratsuka, S, Hayashi, SI, Amizuka, N, Noda, T, Ikeda, K, Shibuya, M. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc Natl Acad Sci USA, 2005;102;14016-14021.
    Pubmed
  50. Noguera-Troise, I, Daly, C, Papadopoulos, NJ, Coetzee, S, Bo-land, P, Gale, NW, Lin, HC, Yancopoulos, GD, Thurston, G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature, 2006;444;1032-1037.
    Pubmed
  51. Oosthuyse, B, Moons, L, Storkebaum, E, Beck, H, Nuyens, D, Brusselmans, K, Van Dorpe, J, Hellings, P, Gorselink, M, Heymans, S, Theilmeier, G, Dewerchin, M, Laudenbach, V, Vermylen, P, Raat, H, Acker, T, Vleminckx, V, Van Den Bosch, L, Cashman, N, Fujisawa, H, Drost, MR, Sciot, R, Bruyninckx, F, Hicklin, DJ, Ince, C, Gressens, P, Lupu, F, Plate, KH, Robberecht, W, Herbert, JM, Collen, D, Carmeliet, P. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet, 2001;28;131-138.
    Pubmed
  52. Osawa, T, Tsuchida, R, Muramatsu, M, Shimamura, T, Wang, F, Suehiro, JI, Kanki, Y, Wada, Y, Yuasa, Y, Aburatani, H, Miyano, S, Minami, T, Kodama, T, Shibuya, M. Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor associated macrophages. Cancer Res, 2013;73;3019-3028.
    Pubmed
  53. P?ez-Ribes, M, Allen, E, Hudock, J, Takeda, T, Okuyama, H, Vi?als, F, Inoue, M, Bergers, G, Hanahan, D, Casanovas, O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 2009;15;220-231.
    Pubmed
  54. Pritchard-Jones, RO, Dunn, DB, Qiu, Y, Varey, AH, Orlando, A, Rigby, H, Harper, SJ, Bates, DO. Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br. J. Cancer, 2007;97;223-230.
    Pubmed
  55. Risau, W. Mechanisms of angiogenesis. Nature, 1997;386;671-674.
    Pubmed
  56. Sakurai, Y, Ohgimoto, K, Kataoka, Y, Yoshida, N, Shibuya, M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci USA, 2005;102;1076-1081.
    Pubmed
  57. Sallinen, H, Anttila, M, Gr?hn, O, Koponen, J, H?m?l?inen, K, Kholova, I, Kosma, VM, Heinonen, S, Alitalo, K, Yl?-Herttuala, S. Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice. Cancer Gene Ther, 2011;18;100-109.
    Pubmed
  58. Sase, H, Watabe, T, Kawasaki, K, Miyazono, K, Miyazawa, K. VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells. J Cell Sci, 2009;122;3303-3311.
    Pubmed
  59. Sato, T, Amano, H, Ito, Y, Eshima, K, Minamino, T, Ae, T, Katada, C, Ohno, T, Hosono, K, Suzuki, T, Shibuya, M, Koizumi, W, Majima, M. NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4+VEGFR1+ cells to the ulcer granulation tissues. Biomed Pharmacother, 2013;67;607-613.
    Pubmed
  60. Sato, Y. The vasohibin family: a novel family for angiogenesis regulation. J Biochem, 2013;153;5-11.
    Pubmed
  61. Sawano, A, Takahashi, T, Yamaguchi, S, Aonuma, T, Shibuya, M. Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor (PlGF), which is related to vascular endothelial growth factor (VEGF). Cell Growth Diff, 1996;7;213-221.
    Pubmed
  62. Schwartz, JD, Rowinsky, EK, Youssoufian, H, Pytowski, B, Wu, Y. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer, 2010;116;1027-1032.
    Pubmed
  63. Shalaby, F, Rossant, J, Yamaguchi, TP, Gertsenstein, M, Wu, XF, Breitman, ML, Schuh, AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature, 1995;376;62-66.
    Pubmed
  64. Shibuya, M, Yamaguchi, S, Yamane, A, Ikeda, T, Tojo, A, Matsushime, H, Sato, M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene, 1990;5;519-524.
    Pubmed
  65. Shibuya, M, Claesson-Welsh, L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res, 2006;312;549-560.
    Pubmed
  66. Shibuya, M. Vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1): a dual regulator for angiogenesis. Angiogenesis, 2006;9;225-230.
    Pubmed
  67. Shibuya, M. Involvement of Flt-1 (VEGFR-1) in cancer and preeclampsia. Proc Jpn Acad Ser B Phys Biol Sci, 2011;87;167-178.
  68. Suri, C, Jones, PF, Patan, S, Bartunkova, S, Maisonpierre, PC, Davis, S, Sato, TN, Yancopoulos, GD. Requisite role of Angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell, 1996;87;1171-1180.
    Pubmed
  69. Takahashi, T, Ueno, H, Shibuya, M. VEGF activates Protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene, 1999;18;2221-2230.
    Pubmed
  70. Takahashi, T, Yamaguchi, S, Chida, K, Shibuya, M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGFA-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells. EMBO J, 2001;20;2768-2778.
    Pubmed
  71. Tammela, T, Zarkada, G, Wallgard, E, Murtomaki, A, Suchting, S, Wirzenius, M, Waltari, M, Hellstrom, M, Schomber, T, Peltonen, R, Freitas, C, Duarte, A, Isoniemi, H, Laakkonen, P, Christofori, G, Yla-Herttuala, S, Shibuya, M, Pytowski, B, Eichmann, A, Betsholtz, C, Alitalo, K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature, 2008;454;656-660.
    Pubmed
  72. Tanaka, K, Yamaguchi, S, Sawano, A, Shibuya, M. Characterization of the extracellular domain in the vascular endothelial growth factor receptor-1 (Flt-1 tyrosine kinase). Jpn J Cancer Res, 1997;88;867-876.
    Pubmed
  73. Thadhani, R, Kisner, T, Hagmann, H, Bossung, V, Noack, S, Schaarschmidt, W, Jank, A, Kribs, A, Cornely, OA, Kreyssig, C, Hemphill, L, Rigby, AC, Khedkar, S, Lindner, TH, Mallmann, P, Stepan, H, Karumanchi, SA, Benzing, T. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation, 2011;124;940-950.
    Pubmed
  74. Verheyen, A, Peeraer, E, Nuydens, R, Dhondt, J, Poesen, K, Pintelon, I, Daniels, A, Timmermans, JP, Meert, T, Carmeliet, P, Lambrechts, D. Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy. Brain, 2012;135;2629-2641.
    Pubmed
  75. Wang, HU, Chen, ZF, Anderson, DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell, 1998;93;741-753.
    Pubmed
  76. Watnick, RS, Cheng, YN, Rangarajan, A, Ince, TA, Weinberg, RA. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell, 2003;3;219-231.
    Pubmed
  77. Wittko, IM, Sch?nzer, A, Kuzmichev, A, Schneider, FT, Shibuya, M, Raab, S, Plate, KH. VEGFR-1 regulates adult olfactory bulb neurogenesis and migration of neural progenitors in the rostral migratory stream in vivo. J Neurosci, 2009;29;8704-8714.
    Pubmed
  78. Xiong, Y, Huo, Y, Chen, C, Zeng, H, Lu, X, Wei, C, Ruan, C, Zhang, X, Hu, Z, Shibuya, M, Luo, J. Vascular endothelial growth factor (VEGF) receptor-2 tyrosine 1175 signaling controls VEGF-induced von Willebrand factor release from endothelial cells via phospholipase C-gamma 1- and protein kinase A-dependent pathways. J Biol Chem, 2009;284;23217-23224.
    Pubmed
  79. Yamauchi, M, Imajoh-Ohmi, S, Shibuya, M. Novel anti-angiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle. Cancer Sci, 2007;98;1491-1497.
    Pubmed
  80. Yan, M, Callahan, CA, Beyer, JC, Allamneni, KP, Zhang, G, Ridgway, JB, Niessen, K, Plowman, GD. Chronic DLL4 blockade induces vascular neoplasms. Nature, 2010;463;E6-7.
    Pubmed
  81. Young, BC, Levine, RJ, Karumanchi, SA. Pathogenesis of preeclampsia. Annu Rev Pathol, 2010;5;173-192.
    Pubmed


This Article

e-submission

Archives