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Pitfalls in the Measurement of Circulating Vascular Endothelial Growth Factor

¹ Institut für Physiologie, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. Fax 49-451-500-4151; e-mail jelkmann{at}physio.mu-luebeck.de.

	Abstract

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
Background: Vascular endothelial growth factor (VEGF) is a protein with antiapoptotic, mitogenic, and permeability-increasing activities specific for vascular endothelium. VEGF mRNA, which has five isoforms, is produced by nonmalignant cells in response to hypoxia and inflammation and by tumor cells in constitutively high concentrations. Because VEGF plays a crucial role in physiological and pathophysiological angiogenesis, measurements of circulating VEGF are of diagnostic and prognostic value, e.g., in cardiovascular failures, inflammatory diseases, and malignancies. However, there are major quantitative differences in the published results. This review attempts to identify reasons for these disparities.

Approach: The literature was reviewed through a Medline search covering 1995 to 2000. A selection of exemplary references had to be made for this perspective overview.

Content: Data are included from studies on healthy humans, gynecological patients, and persons suffering from inflammatory or malignant diseases. The results indicate that competitive immunoassays detect the total amount of circulating VEGF, which enables observations regarding the increase in VEGF in pregnancy and preeclampsia to be made. In these cases, capture immunoassays utilizing neutralizing antibodies are insufficient because of an accompanying increase in VEGF-binding soluble receptors (sFlt-1). Measurements of circulating free VEGF are useful for study of malignant diseases, which are associated with both genetically and hypoxia-induced overproduction of VEGF. The VEGF isoform specificity of the antibodies is also critical because both VEGF₁₂₁ and VEGF₁₆₅ are secreted. It is important to consider that platelets and leukocytes release VEGF during blood clotting.

Conclusions: Future efforts should concentrate on the balance between free VEGF, total VEGF, and sFlt-1. Plasma, rather than serum, should be used for analysis.

	Introduction

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
Vascular endothelial growth factor (VEGF)¹ is a specific mitogen and survival factor for endothelial cells and a key promoter of angiogenesis in physiological and pathophysiological conditions (1)(2). VEGF is required for the normal development of embryonic vasculature, the cyclic growth of blood vessels in the female reproductive tract, and the formation of capillaries during wound repair. Trials in experimental animals and human patients have shown the therapeutic potential of VEGF in coronary or peripheral arterial stenosis. However, VEGF is also involved in abnormal angiogenesis, as seen in proliferative retinopathies, rheumatoid arthritis, psoriasis, and malignancies. In fact, VEGF plays a pivotal role in tumor expansion. It locally initiates permeabilization of blood vessels, extravasation of plasma proteins, invasion of stromal cells, and sprouting of new blood vessels that supply the tumor with O₂ and nutriments and facilitate metastasis. Inhibition of angiogenesis is a novel strategy in antitumor therapy (3)(4).

Initial studies revealed that the lungs, kidneys, heart, and adrenal glands are the dominant sites of expression of the VEGF gene in healthy adult animals (5). Today, it is assumed that all tissues have the potential to produce the growth factor. Its synthesis is stimulated when cells become deficient in O₂ or glucose and in inflammatory reactions. Tumor cells tend to overexpress VEGF constitutively. VEGF acts primarily in a paracrine way and binds to receptors of the basal membranes of the endothelium. Hence, the question arises as to the origin and function of blood-borne VEGF.

Approximately 300 publications dealing with measurements of circulating VEGF for diagnostic and therapeutic monitoring have been published during the past 6 years. However, understanding of the relationship between the rate of the production of VEGF and its concentration in blood is still insufficient. Several techniques for immunoassay of circulating VEGF have been described. If one takes a glance at the results, it becomes obvious that the data vary by up to three orders of magnitude depending on the test applied. This review describes possible reasons for these discrepancies.

Some investigators have used competitive immunoassays, which detect the total amount of circulating VEGF, whereas others have used capture immunoassays with neutralizing antibodies, which detect only free VEGF. In addition, some assays have used antibodies that are specific for single VEGF isoforms. Finally, recent studies have to be taken into account that show that significant amounts of VEGF can be released from platelets and leukocytes during blood sampling and handling.

	Molecular Biology of VEGF

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
The human VEGF gene consists of eight exons and seven introns. Transcriptional activation is mediated by binding of the trans-acting dimeric protein hypoxia-inducible factor-1 (HIF-1/ß) to a hypoxia response element in the human VEGF gene promoter. The HIF-1 subunit is unstable in normoxia because it possesses a PO₂-dependent degradation domain that targets it for ubiquitination. In addition, VEGF mRNA is stabilized in hypoxia. Several proinflammatory cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF-), stimulate VEGF gene expression in a tissue-specific way (2)(4). Recent evidence suggests that the actions of IL-1 and TNF- are also mediated through increased HIF-1 binding to DNA (6). The molecular mechanisms of the increase in VEGF mRNA and VEGF protein production in response to glucose deprivation are not yet understood. Hormones reported to influence VEGF mRNA production include insulin, insulin-like growth factor-1, corticotropin, thyrotropin, and steroidal hormones (7).

At least five isoforms of the protein, composed of 121, 145, 165, 189, and 206 amino acids, can be translated because of alternative VEGF mRNA splicing (2)(4). Glycosylation is essential for efficient secretion. VEGF₁₂₁ is a freely soluble protein that does not bind heparin. VEGF₁₆₅, the predominant isoform, is a heparin-binding basic homodimer of 45 kDa that remains partly bound to the cell surface and the extracellular matrix. The other isoforms do not enter the circulation in significant amounts because they are either bound to the extracellular matrix (VEGF₁₄₅) or are secreted sparingly (VEGF₁₈₉ and VEGF₂₀₆).

VEGF binds with high affinity to two tyrosine kinase receptors, the fms-like tyrosine kinase (Flt-1, VEGFR-1) and the kinase domain receptor (KDR, VEGFR-2), which are produced predominantly by endothelial cells. Flt-1 is also present on trophoblasts and macrophages, whereas KDR is present on hemopoietic stem cells, megakaryocytes, and retinal cells. The production of Flt-1 and KDR increases in response to hypoxia, although this increase is smaller than that of VEGF. Binding of VEGF causes receptor dimerization and autophosphorylation for signaling. The antiapoptotic and mitotic functions of VEGF are mediated by KDR. VEGF₁₆₅ can also bind to neuropilin-type receptors, which may explain why VEGF₁₆₅ is a more potent mitogen than VEGF₁₂₁. A detailed description of the structures and functions of the various VEGF receptors has been provided by Neufeld et al. (4).

The VEGF family of growth factors includes several related molecules, such as placenta growth factor, VEGF-B, VEGF-C, VEGF-D, and others. VEGF (VEGF-A) and its analogs have homologous amino acid sequences and bind to tyrosine kinase receptors of the same class (8)(9). This review is restricted to the measurement of VEGF.

	Methods for Assaying Circulating VEGF

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
Cell proliferation tests, receptor binding assays, or immunoassays can be applied for VEGF quantification. VEGF (>100 ng/L) stimulates the growth of endothelial cells in vitro. Keyt et al. (10) demonstrated that response curves with glycosylated vs nonglycosylated recombinant VEGF isoforms are identical. However, endothelial cell proliferation tests are insufficient for assay of circulating VEGF. Immunoassays are preferred in clinical practice, although they may detect VEGF epitopes, even when the molecule is devoid of biological activity. In-house RIAs with radiolabeled VEGF (11), radioimmunometric assays with radiolabeled monoclonal anti-VEGF antibody (12), and immunochemiluminescence or ELISAs with either polyclonal (13)(14) or monoclonal (15) antibodies or a combination of these (16) have been developed. The primary capture antibody can be replaced by recombinant VEGF receptor molecules for ELISA (17). In addition, commercial methods are available. Compared with bioassays, immunoassays are characterized by low detection limits and greater specificity, reproducibility, and practicability (18).

An international standard preparation of VEGF has not been established. Comparative studies with different recombinant DNA-derived VEGF products have not been carried out with respect to antibody binding affinity and parallelism of dilution curves in immunoassays. The importance of standardization of calibrants has been demonstrated in a WHO study revealing substantial interassay differences in the results obtained with commercial methods for IL-2, IL-6, and TNF- (19).

Regarding the measurement of circulating VEGF, some assays detect only VEGF₁₂₁ (13) or only VEGF₁₆₅ (15), whereas others measure the sum (VEGF_121/165) of these (15)(16)(17). A more crucial point is that capture ELISAs, with recombinant VEGF receptors or neutralizing monoclonal antibodies, selectively detect free VEGF. It remains to be investigated whether changes in the concentration of free VEGF truly reflect VEGF production, relative to degradation rates, or altered binding to carrier proteins alone. A major potential VEGF-binding plasma protein is ₂-macroglobulin, which prevents the growth factor from binding to its receptor (20). However, several investigators have shown that ₂-macroglobulin does not interfere in their assay systems (11)(16). Thus, it is unlikely that ₂-macroglobulin is the main binding protein masking VEGF in immunoassays.

In addition, the soluble form of VEGFR-1, sFlt-1, interacts with circulating VEGF (17)(21)(22). Banks et al. (23) partially purified and sequenced the VEGF-binding activity in plasma samples from pregnant women and demonstrated a novel multimeric receptor complex of 400–550 kDa that bound several VEGF molecules. Sandwich ELISAs with monoclonal antibodies fail to detect the antigen if the epitopes are masked by soluble receptors. Such interference has been described previously with respect to measurements of circulating IL-1, IL-2, IL-6, and TNF- (24). The common observation that the plasma concentrations of soluble receptors for cytokines are high (10–100 µg/L) holds true for sFlt-1 (25). The total concentration of VEGF (14) can be determined by competitive binding assays, i.e., by RIAs or fluorometric ELISAs that require only one epitope located in a region of the molecule that is not occupied by a receptor molecule. Interaction between VEGF and sFlt-1 must also be considered in assays of tissue culture medium from cell lines expressing VEGF receptors (26).

Assays have been marketed for the measurement of total VEGF (detection limits 200 ng/L; Cytokit Red^TM VEGF, CYTimmune Sciences; ACCUCYTE^®, Peninsula Laboratories) or free VEGF_121/165 (detection limits 10 ng/L; Quantikine^®, R&D Systems; CYTELISA^TM, Peninsula Laboratories; hVEGF ELISA, BioSource International). In the competitive binding assay reagent sets for total VEGF, ELISA plates usually are coated with goat anti-rabbit antibodies for capture of polyclonal rabbit anti-human VEGF antibody. VEGF calibrators and samples are then added in a competition reaction with biotinylated human VEGF. Commercial capture ELISA methods for free VEGF use the sandwich technique, in which monoclonal antibody specific for VEGF is precoated onto the plates. After VEGF binding to the immobilized antibody, the enzyme-linked second polyclonal or monoclonal antibody and substrate are added for color development.

Faced with these substantial differences in the assay methods (Table 1 ), it is not surprising that great variations exist when published concentrations of circulating VEGF in healthy human subjects are compared. Measured total VEGF concentrations of 3–25 µg/L have been reported for competitive ELISAs (27)(28)(29), whereas measured concentrations of 1 µg/L have been reported for RIAs (11). The mean concentrations of free VEGF₁₂₁ and VEGF₁₆₅ have been reported as 19 ng/L (13) and 42 ng/L (15), respectively. All of these values are independent of gender. In studies incorporating the most commonly used commercial ELISA (Quantikine), which detects the free isoforms VEGF₁₂₁ and VEGF₁₆₅, plasma values of <9–150 ng/L in healthy subjects have been reported (15)(23)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Higher values have been measured by in-house assays with polyclonal antibodies for VEGF (14). Furthermore, compared with plasma, the reference interval for serum VEGF_121/165 is relatively high, averaging 10–300 ng/L (12)(15)(31)(35)(38)(41)(42).

The differences between plasma vs serum concentrations have been ascribed to the release of VEGF from platelets and other blood cells during clotting. On closer inspection, serum VEGF concentrations reflect blood platelet counts rather than VEGF synthesis by peripheral tissues (17)(30)(31). The serum VEGF concentration further increases with clotting duration and temperature (17). In addition to platelets, leukocytes can also secrete VEGF (35)(43). Separate measurements of free VEGF_121/165 in blood cells (445 ng/L) and plasma (19 ng/L) have underscored the relevance of blood cell-derived VEGF in serum samples.

Citrated, EDTA-treated, or heparinized plasma processed in glass tubes is the material of choice for measurement of VEGF. Plasma should be frozen (-80 °C) within 1 h after venipuncture (31). Alternatively, blood may be collected in CTAD tubes, which contain citrate, theophylline, adenosine, and dipyridamole for platelet stabilization (44). In the following discussion, references will be restricted to measurements of VEGF in plasma, rather than serum, whenever possible.

	Circulating VEGF in Pregnancy

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
During pregnancy VEGF is essential for the proliferation of trophoblasts, the development of embryonic vasculature, and the growth of both maternal and fetal blood vessels in the uterus. Using a competitive RIA, Anthony et al. (11) and Evans et al. (45) demonstrated that maternal serum VEGF increases during the first trimester of pregnancy (to 2.1 µg/L compared with 1.1 µg/L in nonpregnant women). Capture ELISAs with neutralizing antibodies neither detect this increase, which is attributable to sFlt-1 produced by the placenta (22)(23), nor can they recover VEGF added to pregnancy samples (11). Measurements of total VEGF in EDTA plasma by nonradioactive competitive immunoassays yielded results of 12 µg/L in normal pregnancies antepartum and 33 µg/L in gestational age-matched patients with preeclampsia (46). Other investigators have reported similar results (47), which support earlier evidence obtained by a polyclonal antibody-based capture ELISA in serum samples (48). Placental VEGF overproduction in response to local hypoxia and inflammatory cytokines is involved in the etiology of preeclampsia, which complicates 5–10% of all pregnancies. An additional observation of diagnostic value is the increase in circulating free VEGF after administration of human chorionic gonadotropin to patients at risk from ovarian hyperstimulation syndrome (29)(49)(50). Measurements of total serum VEGF produced similar results in one study (27), but not in another (29).

	Circulating VEGF in Response to Hypoxia and Inflammation

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
Maloney et al. (51) found that the concentration of free VEGF_121/165 is not increased in the plasma of mountaineers at extreme altitudes (14 200 feet) in association with hypoxia or acute mountain sickness. Accordingly, the increased serum VEGF concentrations measured in athletes training at high altitudes have been related to activation of the immune system rather than to hypoxic stress (52). Acute tissue hypoxia caused by cigarette smoking is not a major stimulus for increased plasma free VEGF_121/165 concentrations (36). However, the increased VEGF concentrations in serum from the superior vena cava and the systemic arteries of children with cyanotic congenital heart disease (53) could indicate local stimulation of VEGF synthesis in response to systemic hypoxia.

Ischemia of the heart produces an acute increase in serum free VEGF_121/165 concentrations (42). Administration of heparin to patients with acute myocardial infarction rapidly lowers VEGF values (54). Disturbances of the peripheral microcirculation can also lead to increased concentrations of circulating VEGF as demonstrated in patients with chronic venous disease (37) or sickle cell anemia (34). Whether the increased concentrations of circulating free VEGF seen in diabetic patients (25)(36)(55) are attributable to peripheral hypoxia in association with angiopathies or to impaired glucose metabolism remains to be investigated. Importantly, Lip et al. (25) reported a significant decrease in plasma free VEGF after successful laser treatment in patients with proliferative retinopathy secondary to diabetes or ischemic retinal vein occlusion.

VEGF promotes inflammatory processes by causing vascular leakage and mobilizing leukocytes. Increased concentrations of free VEGF have been measured in a variety of autoimmune and infectious inflammatory diseases, including rheumatoid arthritis (56), POEMS syndrome (57), and Kawasaki disease (58). This increase may be produced not only by VEGF release from leukocytes and platelets in circulation but also by exudation of the cytokine into the circulation from inflamed organs.

	VEGF in Malignancies

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
Angiogenesis is controlled by a fine local balance between activating and inhibiting mediators (3). Increased production of VEGF mRNA and synthesis of VEGF protein are critical in tumor angiogenesis. Tumor cell-specific genetic alterations lead to VEGF overproduction, even under normoxic conditions. On the basis of ELISA measurements with impure VEGF calibrators and polyclonal antibodies, Kondo et al. (59) first recognized the potential of VEGF as a serum diagnostic marker for malignant diseases. Increased serum concentrations of free VEGF have indeed been measured in various types of cancer, including brain, lung, gastrointestinal, hepatobiliary, renal, ovarian, and others. However, today it is clear that VEGF found in serum is, to a large extent, released from platelets during blood clotting (30)(31). Because blood platelets in tumor patients contain more releasable VEGF than platelets from healthy persons, Lee et al. (60) have argued that serum is more useful than plasma in the diagnosis and follow-up of malignancies. However, it is almost impossible to carry out interlaboratory comparisons of VEGF serum data, mainly because the procedures for blood handling are not standardized with respect to clotting material, duration, and temperature. Therefore, although we previously have shown that the concentration of free VEGF_121/165 is greatly increased in the serum of patients with carcinomas or sarcomas and decreases after successful chemotherapy (41), given the above problems the advice of Banks et al. (31) to use plasma for assay is more accurate.

Careful reexamination using plasma samples has confirmed the concept that the concentration of circulating free VEGF_121/165 is increased in malignant disease (44)(61). Studies in patients with breast (38), gastrointestinal (62), colorectal (39), or prostate cancer (33) and melanoma (40) have shown that plasma free VEGF_121/165 is increased further on development of metastasis. Although values rarely exceeded 500 ng/L in these studies, extremely high free VEGF_121/165 concentrations (up to 463 µg/L) have been reported for patients with leukemias or solid hematological tumors (63). A recent study indicated that an angiogenic profile can be established for tumor patients by measuring the plasma concentrations of the cytokines VEGF, hepatocyte growth factor, basic fibroblast growth factor, TNF-, and transforming growth factor-ß. There is a regular relationship between the concentrations of circulating VEGF and hepatocyte growth factor and the extension of epithelial carcinomas. Basic fibroblast growth factor concentrations usually are increased in lung carcinoma, TNF- concentrations in liver carcinoma, and both cytokines in breast carcinomas (61). These cytokines may be valuable diagnostic and prognostic markers at initial presentation and during therapy of tumor patients.

	Perspectives

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 
VEGF is important in the local control of angiogenesis and vascular permeability. Pharmacotherapeutic trials and genetic engineering have already been performed in attempts to stimulate VEGF-driven angiogenesis in vascular failure and to inhibit this process in expanding tumors. However, several questions still remain with respect to the role of VEGF as a circulating hormone. The plasma concentration of free VEGF usually is very low in healthy subjects. The low concentration of this growth factor could be important in maintaining viability of the endothelium and basic transport across the endothelial barrier. However, most VEGF receptors are located on the basal membranes, thus rendering plasma VEGF superfluous. There are two main stores for plasma VEGF. One storage site is platelets, which take up VEGF and release it on activation in vivo or in vitro. Therefore, serum is not recommended for assay of VEGF. The other storage site is plasma proteins, namely ₂-macroglobulin and sFlt-1, which bind VEGF. Whether binding of VEGF to ₂-macroglobulin is a regulatory process still needs to be investigated. The VEGF-binding capacity of the sFlt-1 fraction in plasma increases greatly during pregnancy. The simultaneous increase in circulating VEGF is detectable in competitive immunoassays but not in capture ELISAs with neutralizing antibodies. Few reports are available concerning the measurement of sFlt-1 and the total pool of VEGF in plasma. Intensive research is required to improve understanding of the balance between free VEGF, total VEGF, and its binding proteins. It seems likely that ₂-macroglobulin and sFlt-1 target VEGF for inactivation, although some hormones are protected from metabolism and renal clearance by binding to carrier proteins. In malignancy and inflammatory diseases, VEGF gene expression is greatly stimulated. Here, plasma VEGF appears to escape from sFlt-1 binding. Genetically determined overproduction of VEGF by tumor cells is thought to be more important than hypoxia-induced VEGF gene expression, which is of interest for therapeutic strategies to improve tumor oxygenation. Measurement of plasma VEGF is expected to play an increasing role in the diagnosis of patients suffering from malignancies and monitoring of therapy.

	Acknowledgments

 
I thank Dr. Bernhard F. Gibbs for linguistic improvement of the manuscript. My studies are supported by the Deutsche Forschungsgemeinschaft (SFB 367-C8).

	Footnotes

 
¹ Nonstandard abbreviations: VEGF, vascular endothelial growth factor; HIF-1, hypoxia-inducible factor-1; IL, interleukin; TNF-, tumor necrosis factor ; Flt-1, fms-like tyrosine kinase; VEGFR, VEGF receptor; KDR, kinase domain receptor; and sFlt-1, soluble Flt-1.

	References

Top Abstract Introduction Molecular Biology of VEGF Methods for Assaying Circulating... Circulating VEGF in Pregnancy Circulating VEGF in Response... VEGF in Malignancies Perspectives References

 

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