J Korean Neurosurg Soc.  2016 Sep;59(5):442-448. 10.3340/jkns.2016.59.5.442.

Systemic Expression of Vascular Endothelial Growth Factor in Patients with Cerebral Cavernous Malformation Treated by Stereotactic Radiosurgery

• Park SJ
• Park SH

• KMID: 2351711
• DOI: http://doi.org/10.3340/jkns.2016.59.5.442

Abstract

OBJECTIVE
Increased expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), is associated with the pathogenesis of cerebral cavernous malformations (CCMs). The purpose of this study was to investigate plasma levels of VEGF in normal subjects and in patients with CCM and to evaluate change in these levels following stereotactic radiosurgery (SRS).
METHODS
Peripheral venous blood was collected from 6 patients with CCM before SRS using Gamma Knife and at the 1 week, 1 month, 3month, and 6 month follow-up visits. Plasma VEGF levels were measured using commercially available enzyme-linked immunosorbent assay kits. Peripheral blood samples were obtained from 10 healthy volunteers as controls.
RESULTS
Mean plasma VEGF level of 41.9 pg/mL (range, 11.7-114.9 pg/mL) in patients with CCM at baseline was higher than that of the healthy controls (29.3 pg/mL, range, 9.2-64.3 pg/mL), without significant differences between CCM patients and controls (p=0.828). Plasma VEGF level following SRS dropped to 24.6 pg/mL after 1 week, and decreased to 18.5 pg/mL after 1 month, then increased to 24.3 pg/mL after 3 months, and 32.6 pg/mL after 6 months. Two patients suffering from rebleeding after SRS showed a higher level of VEGF at 6 months after SRS than their pretreatment level.
CONCLUSION
Plasma VEGF levels in patients with CCM were elevated over controls at baseline, and decreased from baseline to 1 month after SRS and increased further for up to 6 months. Theses results indicated that anti-angiogenic effect of SRS might play a role in the treatment of CCMs.

Keyword

Cavernous malformation; Gamma Knife; Stereotactic radiosurgery; Vascular endothelial growth factor

MeSH Terms

Angiogenesis Inducing Agents
Enzyme-Linked Immunosorbent Assay
Follow-Up Studies
Healthy Volunteers
Hemangioma, Cavernous, Central Nervous System*
Humans
Plasma
Radiosurgery*
Vascular Endothelial Growth Factor A*
Angiogenesis Inducing Agents
Vascular Endothelial Growth Factor A

Figure

• 

  Fig. 1 Plasma concentrations of vascular endothelial growth factor (VEGF) in controls and patients with cerebral cavernous malformation before and after stereotactic radiosurgery (SRS).

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  Fig. 2 Plasma concentrations of vascular endothelial growth factor (VEGF) in patients with cerebral cavernous malformation after stereotactic radiosurgery (SRS).

• 

  Fig. 3 T2-weighted (A) and gradient echo (B) magnetic resonance image (MRI) obtained in a 22-year-old woman with a cerebral cavernous malformation on midbrain. Stereotactic radiosurgery (SRS) was performed with a margin dose of 13 Gy to the 50% isodose line. The T2-weighted (C), gradient echo (D) MRI obtained 30 months after SRS shows a rebleeding on midbrain. Plasma vascular endothelial growth factor (VEGF) concentrations increased from 12.35 pg/mL to 78.56 pg/mL 6 months after SRS.

• 

  Fig. 4 Comparison of plasma vascular endothelial growth factor (VEGF) levels in patients with/without rebleeding after stereotactic radiosurgery (SRS) for cerebral cavernous malformation.

Reference

1. Bobik A, Campbell JH. Vascular derived growth factors : cell biology, pathophysiology, and pharmacology. Pharmacol Rev. 1993; 45:1–42. PMID: 8475168.

2. Brauer MJ, Zhuang G, Schmidt M, Yao J, Wu X, Kaminker JS, et al. Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies. Clin Cancer Res. 2013; 19:3681–3692. PMID: 23685835.

3. Brogi E, Wu T, Namiki A, Isner JM. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation. 1994; 90:649–652. PMID: 8044933.

4. Challa VR, Moody DM, Brown WR. Vascular malformations of the central nervous system. J Neuropathol Exp Neurol. 1995; 54:609–621. PMID: 7666048.

5. Clatterbuck RE, Moriarity JL, Elmaci I, Lee RR, Breiter SN, Rigamonti D. Dynamic nature of cavernous malformations : a prospective magnetic resonance imaging study with volumetric analysis. J Neurosurg. 2000; 93:981–986. PMID: 11117871.

6. Criscuolo GR, Merrill MJ, Oldfield EH. Further characterization of malignant glioma-derived vascular permeability factor. J Neurosurg. 1988; 69:254–262. PMID: 3134521.

7. 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. PMID: 1312256.

8. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res. 2000; 55:15–35. discussion 35-36. PMID: 11036931.

9. Houtteville JP. Brain cavernoma : a dynamic lesion. Surg Neurol. 1997; 48:610–614. PMID: 9400644.

10. Jung KH, Chu K, Jeong SW, Park HK, Bae HJ, Yoon BW. Cerebral cavernous malformations with dynamic and progressive course : correlation study with vascular endothelial growth factor. Arch Neurol. 2003; 60:1613–1618. PMID: 14623736.

11. Kappel A, Rönicke V, Damert A, Flamme I, Risau W, Breier G. Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice. Blood. 1999; 93:4284–4292. PMID: 10361126.

12. Karlsson B, Kihlström L, Lindquist C, Ericson K, Steiner L. Radiosurgery for cavernous malformations. J Neurosurg. 1998; 88:293–297. PMID: 9452238.

13. Kondziolka D, Lunsford LD, Flickinger JC, Kestle JR. Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg. 1995; 83:825–831. PMID: 7472550.

14. Kraft A, Weindel K, Ochs A, Marth C, Zmija J, Schumacher P, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999; 85:178–187. PMID: 9921991.

15. Little JR, Awad IA, Jones SC, Ebrahim ZY. Vascular pressures and cortical blood flow in cavernous angioma of the brain. J Neurosurg. 1990; 73:555–559. PMID: 2398387.

16. Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Jungreis CA, Maitz AH, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991; 75:512–524. PMID: 1885968.

17. Machein MR, Kullmer J, Rönicke V, Machein U, Krieg M, Damert A, et al. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol. 1999; 25:104–112. PMID: 10215998.

18. Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A. 1998; 95:15809–15814. PMID: 9861052.

19. Monacci WT, Merrill MJ, Oldfield EH. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol. 1993; 264(4 Pt 1):C995–C1002. PMID: 8476026.

20. Nagy G, Razak A, Rowe JG, Hodgson TJ, Coley SC, Radatz MW, et al. Stereotactic radiosurgery for deep-seated cavernous malformations : a move toward more active, early intervention. Clinical article. J Neurosurg. 2010; 113:691–699. PMID: 20433275.

21. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol. 1998; 341:309–315. PMID: 9543253.

22. Notelet L, Houtteville JP, Khoury S, Lechevalier B, Chapon F. Proliferating cell nuclear antigen (PCNA) in cerebral cavernomas : an immunocytochemical study of 42 cases. Surg Neurol. 1997; 47:364–370. PMID: 9122841.

23. Nyáry I, Major O, Hanzély Z, Szeifert GT. Histopathological findings in a surgically resected thalamic cavernous hemangioma 1 year after 40-Gy irradiation. J Neurosurg. 2005; 102(Suppl):56–58. PMID: 15662782.

24. Park SH, Hwang JH, Hwang SK. Change in plasma vascular endothelial growth factor after gamma knife radiosurgery for meningioma : a preliminary study. J Korean Neurosurg Soc. 2015; 57:77–81. PMID: 25733986.

25. Pozzati E, Acciarri N, Tognetti F, Marliani F, Giangaspero F. Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery. 1996; 38:662–669. discussion 669-670. PMID: 8692382.

26. Robinson JR, Awad IA, Little JR. Natural history of the cavernous angioma. J Neurosurg. 1991; 75:709–714. PMID: 1919692.

27. Robinson JR Jr, Awad IA, Zhou P, Barna BP, Estes ML. Expression of basement membrane and endothelial cell adhesion molecules in vascular malformations of the brain : preliminary observations and working hypothesis. Neurol Res. 1995; 17:49–58. PMID: 7746343.

28. Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of angiogenic factors and structural proteins in central nervous system vascular malformations. Neurosurgery. 1996; 38:915–924. discussion 924-925. PMID: 8727816.

29. Shifren JL, Doldi N, Ferrara N, Mesiano S, Jaffe RB. In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and myocytes, but not vascular endothelium : implications for mode of action. J Clin Endocrinol Metab. 1994; 79:316–322. PMID: 8027247.

30. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992; 359:843–845. PMID: 1279431.

31. Sonstein WJ, Kader A, Michelsen WJ, Llena JF, Hirano A, Casper D. Expression of vascular endothelial growth factor in pediatric and adult cerebral arteriovenous malformations : an immunocytochemical study. J Neurosurg. 1996; 85:838–845. PMID: 8893722.

32. Strugar JG, Criscuolo GR, Rothbart D, Harrington WN. Vascular endothelial growth/permeability factor expression in human glioma specimens : correlation with vasogenic brain edema and tumor-associated cysts. J Neurosurg. 1995; 83:682–689. PMID: 7674019.

33. Sure U, Butz N, Schlegel J, Siegel AM, Wakat JP, Mennel HD, et al. Endothelial proliferation, neoangiogenesis, and potential de novo generation of cerebrovascular malformations. J Neurosurg. 2001; 94:972–977. PMID: 11409527.

34. Terman B, Khandke L, Dougher-Vermazan M, Maglione D, Lassam NJ, Gospodarowicz D, et al. VEGF receptor subtypes KDR and FLT1 show different sensitivities to heparin and placenta growth factor. Growth Factors. 1994; 11:187–195. PMID: 7734144.

35. Uranishi R, Baev NI, Ng PY, Kim JH, Awad IA. Expression of endothelial cell angiogenesis receptors in human cerebrovascular malformations. Neurosurgery. 2001; 48:359–367. discussion 367-368. PMID: 11220380.

36. Wizigmann-Voos S, Breier G, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995; 55:1358–1364. PMID: 7533661.