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PEDIATRICS Vol. 111 No. 2 February 2003, pp. 358-363

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

Kimberly L. Jones, MD*,¶, Henry F. Krous, MD{ddagger}, Julie Nadeau, RN{ddagger}, Brian Blackbourne, MD§, H. Ronald Zielke, PhD|| and David Gozal, MD*

* Kosair Children’s Hospital Research Institute, Departments of Pediatrics, Pharmacology, and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
{ddagger} Departments of Pathology and Pediatrics, University of California at San Diego, School of Medicine, San Diego, California
§ Office of the Medical Examiner, County of San Diego, San Diego, California
|| Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Section of Pediatric Pulmonology, Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objectives. Recurrent hypoxemia has been proposed as an important pathophysiological mechanism underlying sudden infant death syndrome (SIDS). However, conflicting results emerged when xanthines were used as markers for hypoxia. The vascular endothelial growth factor (VEGF) gene is highly sensitive to changes in tissue partial oxygen tension, and changes in genomic and protein expression occur even after changes in oxygenation within the physiologic range.

Methods. For determining whether hypoxia precedes SIDS, VEGF levels were measured using an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) of 51 SIDS infants and in 33 additional control infants who died of an identifiable cause. In addition, 6 rats that had a chronically implanted catheter in the lateral ventricle were exposed to a short hypoxic challenge, and VEGF concentrations were measured in CSF at various time points for 24 hours. Another set of 6 rats were killed with a pentobarbital overdose, and VEGF CSF levels were obtained at different time points after death.

Results. Mean VEGF concentrations in CSF were 308.2 ± 299.1 pg/dL in the SIDS group and 85.1 ± 82.9 pg/dL in those who died of known causes. Mean postmortem delay averaged 22 hours for both groups. In rat experiments, hypoxic exposures induced time-dependent increases in VEGF, peaking at 12 hours and returning to baseline at 24 hours. Postmortem duration in the animals was associated with gradual increases in VEGF that reached significance only at 36 hours.

Conclusions. We conclude that VEGF CSF concentrations are significantly higher in infants who die of SIDS. We postulate that hypoxia is a frequent event that precedes the sudden and unexpected death of these infants.

Key Words: hypoxia • sudden infant death syndrome • vascular endothelial growth factor

Abbreviations: SIDS, sudden infant death syndrome • VEGF, vascular endothelial growth factor • CSF, cerebrospinal fluid • SD, standard deviation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In recent years, the incidence of sudden infant death syndrome (SIDS) has decreased primarily as a result of public campaigns aiming to reduce prone sleeping position in infants.1 However, SIDS remains the major cause of death in seemingly healthy infants.2 In addition to prone sleep position, risk factors for SIDS include parental smoking, overheating, and socioeconomic status, and, to some extent, there is an apparent seasonal variation with peaks occurring in winter months.3,4 Although the precise mechanisms underlying SIDS remain undefined, the hypothesis that recurrent or prolonged hypoxemia may precede the fatal event has gained significant attention in the past decades. Nevertheless, such hypothesis has not been demonstrated or refuted definitively.5–11

In search for more conclusive evidence of hypoxia in SIDS, biochemical markers indicative of hypoxemia, such as lactate or xanthines, were examined in SIDS cohorts.5–10 However, although xanthine levels were elevated in many SIDS cases, the sensitivity of this assay was reduced by the fact that other conditions, such as infections, could lead to similar elevations. In addition, multiple and/or severe hypoxic events that lead to adenosine triphosphate degradation and accumulation of xanthines in the tissue or body fluid of interest would be required for xanthine elevation.6,8

Neuronal apoptosis was significantly induced within regions of the brainstem and hippocampus in SIDS cases.11 Because development of DNA laddering and degradation require at least several hours, the increased apoptotic staining found in such brain areas suggested that hypoxia preceded infant death by at least a few hours.11

Sustained or intermittent hypoxia in mammalian tissues will promote formation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF is an endothelial cell-specific mitogen that increases peripheral oxygen delivery by stimulating angiogenesis, therefore improving tissue capillary density. VEGF-stimulated angiogenesis involves endothelial cell migration, proliferation, and differentiation, as well as proteolysis of the extracellular matrix.12 Increased VEGF protein expression occurs after hypoxia by enhanced transcriptional regulation of the VEGF gene through binding of the hypoxia-inducible factor-1 to a hypoxic responsive element in the 5' flanking region of the VEGF gene.13 VEGF expression is induced in vivo in various models of ischemia in brain, heart, lung and certain tumors.14–22 However, even small changes in tissue oxygen tension within the physiologic range can lead to substantial alterations in VEGF expression.17 The unique activity of this factor in the regulation and proliferation of vascular beds allows VEGF to be measured in body fluids, such as serum, vitreous humor, and cerebrospinal fluid (CSF),18,19,21 where it can serve as a marker of tumor recurrence or as a prognostic factor.18,19,21 Furthermore, circulating levels of VEGF are elevated in the serum of experimentally induced hypoxia in animals,23 as well as in patients with obstructive sleep apnea.24,25 On the basis of the premise that biologically significant hypoxemia will occur before SIDS, we hypothesized that VEGF concentrations would be elevated in body fluids of SIDS infants.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
SIDS and Control Samples
Serum, CSF, and vitreous humor samples that had been accessioned by the San Diego SIDS research project and from the National Institute of Child Health and Human Development Brain & Tissue Bank at the University of Maryland were obtained at the time of autopsy from the medical examiner of San Diego County and the state of Maryland. The cause of death was defined as SIDS when it occurred in infants younger than 1 year, was unexpected by history, and thorough death scene investigation and postmortem examination failed to demonstrate an adequate cause of death.26 Both the death scene investigations and autopsies were performed in accordance with well-established guidelines.26,27 Cases whose cause of death was clearly established served as controls. Blood was collected in plain tubes and centrifuged, and serum was frozen at –55°C. The average time from autopsy to freezing was 1 to 2 hours. CSF was obtained in sterile conical tubes and frozen at –55°C within 30 minutes to 1.5 hours from collection. Vitreous humor was obtained in sterile conical tubes and refrigerated for approximately 1 to 2 weeks before being frozen.

Animal Experiments
For determining the time course of VEGF increases after a hypoxic exposure, 6 adult male Sprague Dawley rats were anesthetized with pentobarbital sodium (60 mg/kg intraperitoneally), and a catheter was placed in the lateral ventricle using standard stereotaxic coordinates.28 The catheter was secured with sutures, tunneled under the skin into the dorsal neck region, sealed with heat, and stored in a plastic cap sutured to the skin. After rats recovered from anesthesia, as evidenced by full resumption of grooming, ingestive, and other behaviors, CSF was sampled before and at 0, 1, 6, 12, and 24 hours after a 15-minute exposure to 6% oxygen in an environmental chamber. For investigating the effect of postmortem delay on VEGF levels, another set of 6 rats were instrumented under general anesthesia. An overdose of pentobarbital was then given, and samples of CSF were obtained at 0, 6, 12, 24, and 36 hours after death. Environmental temperature was controlled at 24°C to 25°C throughout the experiments.

VEGF Enzyme-Linked Immunosorbent Assay
Assays for VEGF concentrations were performed by enzyme-linked immunosorbent assay using a commercially available kit (R&D Systems, Inc, Minneapolis, MN). The lower sensitivity of the test is <3 pg/mL, and linear results are obtained at a range of 7.0 to 2000 pg/mL. With each assay, calibration curves were performed and showed linear sensitivity within the stipulated range as well as reproducibility agreement at r = 0.99.

Data Analysis
Data are shown as mean ± standard deviation (SD). Data analysis was performed using 2-tailed t tests or {chi}2, with P < 0.05 considered as statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects ranged in age from 3 days to 193 days of age, and their mean age was similar in the SIDS and control groups. The average estimated postmortem interval was 22.2 hours for both groups.

Vitreous Humor
Thirty-three samples that included 21 SIDS cases were available for analysis. The range of VEGF concentrations was 0 to 403.2 pg/mL in SIDS and 0 to 94 pg/mL in the 12 controls. However, 25 of the 33 samples (18 SIDS and 7 controls) had no detectable levels of VEGF. To examine further the potential reasons accounting for so many undetectable values in the vitreous humor, we performed protein gel electrophoresis and found evidence for protein degradation as evidenced by the absence of protein banding.

Serum
Twenty-two samples were assayed for VEGF levels, 17 of which were SIDS cases. As with the vitreous humor samples, VEGF levels ranged from 0 to 1523 pg/mL in SIDS and from 0 to 116 pg/mL in controls. In 12 of the 22 samples (10 SIDS and 2 controls), no detectable levels of VEGF were present. Protein electrophoresis confirmed protein degradation in these samples.

CSF
Fifty-one CSF samples from SIDS cases and 33 samples from control cases were available for analysis. Mean ages were similar for the 2 groups (3.2 ± 2.5 months for the SIDS group and 3.7 ± 3.1 month for controls; not significant). In the control group, the final causes of death included intestinal infarction, cardiomyopathies and congenital heart disease, pneumonia, accidental suffocation, and sepsis (see Table 1). In SIDS cases, no cause of death could be found. When present, the most frequent histologic changes noted at autopsy in SIDS cases included intrathoracic petechiae and pulmonary congestion. Body position was also noted in both groups, but no correlation was found between position at time of death and VEGF levels, with approximately 50% of SIDS cases being found in the prone position. Mean VEGF concentrations in CSF were 308.2 ± 299.1 pg/dL in the SIDS group and 85.1 ± 82.9 pg/dL in those who died of known causes (P < .00001; Fig 1). On the basis of a VEGF concentration of 200 pg/mL in CSF (corresponding to the mean + 2 SD of control), 21 SIDS cases had normal levels, whereas 2 control cases had VEGF levels >200 pg/mL (P < .001). No significant relationships were found between VEGF concentration and the estimated delays between time of death and autopsy (r2 = 0.09; not significant).


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  		TABLE 1. Identified Causes of Death in 33 Infants Serving as Control Cases

 


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  		Fig 1. Individual VEGF concentrations in CSF samples of 51 SIDS ({circ}) and 33 controls ({blacksquare}). The line indicates the mean + 2 SD for controls. SIDS versus controls: P < .00001.

 
Figure 2A shows the time course of VEGF concentrations in the CSF of rats exposed to 15 minutes of hypoxia. Baseline normoxic VEGF concentrations in CSF were 9.2 ± 2.4 pg/dL. Increases in VEGF occurred at 6 hours, peaked at 12 hours (122.4 ± 7.8 pg/dL; P < .001 vs baseline), and returned to baseline values within 24 hours. Sampling time after death seemed to be associated with a small, albeit significant, spurious elevation of VEGF in CSF at 36 hours postmortem (Fig 2B).



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  		Fig 2. A, Time course of VEGF concentrations in CSF of 6 rats exposed to a 15-minute challenge with 6% oxygen (at arrow). Time-dependent increases in VEGF levels occurred at 6 hours, peaked at 12 hours, and returned to baseline at 24 hours. (*P < .001 vs normoxic baseline). B, Time course of postmortem VEGF concentrations in CSF of 6 rats after pentobarbital overdose. Small increases in VEGF occurred over time after death but became significantly different from baseline only at 36 hours (*P < .01).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we present novel evidence suggesting that a single or multiple hypoxic events may precede death in many SIDS cases. We propose that such hypoxic episodes preceded infant death by at least several hours, because this would be the minimal time required for genomic transcription and expression of VEGF protein after activation and nuclear binding of the hypoxic sensing elements mediating VEGF gene regulation. Thus, at least in a substantial proportion of SIDS occurrences, the mechanisms that lead to such SIDS deaths seem to involve emergence of conditions that lead to development of low oxygen tissue tension. Obviously, the pathophysiological characteristics of such conditions are unknown. However, on the basis of several reports of infants who died of SIDS while on cardiorespiratory monitors, bradycardia, sometimes preceded by tachycardia, was the most consistent pattern of cardiac activity29,30 and could represent a documented physiologic manifestation of hypoxia. The cause of hypoxemia in the absence of prolonged central apnea could be ascribed to other mechanisms, such as upper airway obstruction or rebreathing.

What is the evidence for hypoxia in SIDS? As mentioned, the early studies by Naeye31 assigned the major impetus for an abnormality of respiratory control causing subsequent hypoventilation and hypoxia and leading to SIDS. More recent work has attempted to confirm that hypoxemia was indeed present in SIDS infants before their terminal event. For example, Ozawa et al32 showed significant decreases in tyrosine hydroxylase immunoreactivity in catecholaminergic neurons of the basal ganglia of SIDS cases compared with age-matched control subjects, suggesting that chronic or intermittent severe hypoxia may have occurred. However, although it is clear that the tyrosine hydroxylase gene exhibits hypoxia-sensitive regulatory domains, in a cell line such as that derived from pheochromocytoma (PC12 cell line), hypoxia enhanced rather than reduced tyrosine hydroxylase gene expression33,34 such that the mechanisms underlying the findings of Ozawa et al35 remain undefined and could be related to the posthypoxic gliosis. In an extensive examination of SIDS cohorts, the degradation of adenosine triphosphate during conditions of limited tissue oxygen availability was examined by assaying xanthine levels in various body fluids.36 In agreement with such plausible biochemical cascade, elevated hypoxanthine levels in the vitreous humor of SIDS victims were previously reported6–10 and more likely would be attributable to intermittent hypoxic events than to chronic hypoxia37; however, this group of investigators also recently reported that although hypoxanthine vitreous humor concentrations were significantly higher in SIDS victims compared with cases of violent death and deaths as a result of heart and/or lung disease, such differences were not present when SIDS cases were compared with those resulting from an infectious process.38 Furthermore, others have assigned the elevation of xanthine concentrations to adenine nucleotide hydrolysis possibly resulting from antemortem hypoxia in most deaths.39 Thus, the currently available evidence does neither irrevocably demonstrate nor refute the hypothesis that hypoxia indeed is present either intermittently or at least at 1 point in time before the fatal SIDS event.

By virtue of the limitations imposed by either assessment of gliosis or xanthine levels toward establishment of a more definitive hypoxic cause of SIDS, it was necessary to explore genomic alterations that specifically occur in response to a hypoxic stimulus. One such direction involved the assessment of erythropoietin concentrations in the blood of infants who die of SIDS.40 Indeed, similar to the VEGF gene, the erythropoietin gene contains cis-acting elements with cognate hypoxia response elements that can activate transcription.41 One such hypoxia response element is hypoxia-inducible factor 1, a transcription factor that mediates changes in gene expression in response to changes in oxygen concentration.42 Thus, both erythropoietin and VEGF would be expected to display significant expression enhancements in response to hypoxia. However, the magnitude, duration, and type (intermittent vs sustained) of hypoxia and the tissue being examined would be the major determinants in dictating our ability to detect changes in expression of either VEGF or erythropoietin that would putatively occur after hypoxic events in infants who ultimately die of SIDS. Similar to the current findings, Le Cam-Duchez et al40 found that SIDS infants had higher erythropoietin serum concentrations compared with the control group, thereby suggesting that a hypoxic event occurred before the unexpected death of these infants.

VEGF protein upregulation has been previously demonstrated in animal models subjected to environmental hypoxia or to a variety of pathologic conditions in which tissue oxygen limitation occurs, such as tumor, ischemic stroke, and pulmonary hypertension.14,18–23,43 The increase in VEGF tissue levels becomes detectable 6 hours after application of the hypoxic challenge,13 and the present study not only extends these observations to the CSF but also demonstrates that the VEGF response to a short hypoxic exposure will peak at 12 hours and return to baseline within 24 hours. In humans, a rise in circulating VEGF can be observed 1 to 2 days after strenuous exercise at moderate altitude.12 On the basis of the premise of recurrent hypoxia over hours to days before the fatal event in SIDS, one would expect that VEGF levels increased in measurable body fluids, such as serum, urine, vitreous, and CSF. Unfortunately, urine is usually not available at the time of postmortem evaluation and can be obtained in only 40% of SIDS.26 Another limitation of the VEGF assay and of any other protein, for that matter, is the potential for degradation of the protein when samples are not collected immediately and preserved in optimal conditions so as to prevent endogenous protease activity. Thus, VEGF levels of our serum and vitreous humor were unreliable, and additional electrophoretic analysis confirmed extensive protein degradation in a substantial proportion of such samples. To the best of our knowledge, no studies to date have examined VEGF levels in the CSF of humans. The relatively low concentration of proteases in CSF would account for the improved stability of the VEGF protein in these samples, and the elevated VEGF levels found in the CSF of SIDS cases concurs with the hypothetical framework delineated above and suggests that 1 or more hypoxic events occur over several hours to days before the final event as reflected by the time needed for gene upregulation and subsequent protein expression and release to body fluids. We postulate that the elevated VEGF concentrations found in 30 of 51 SIDS CSF samples provides additional incentive to delineation of pathophysiological mechanisms that include hypoxia in the cascade of events that lead to SIDS.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the National Institutes of Health (HL-63912, HL-65270, HL-66358) (to Dr Gozal), the American Heart Association (0050442N), and the Commonwealth of Kentucky Research Challenge Trust Fund.


   FOOTNOTES
 
Received for publication Feb 26, 2002; Accepted Aug 20, 2002.

Reprint requests to (D.G.) Kosair Children’s Hospital Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 S. Preston St, Ste 321, Louisville, KY 40202. E-mail: david.gozal{at}louisville.edu


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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