Accelerated growth of hemangioblastoma in pregnancy: the role of proangiogenic factors and upregulation of hypoxia-inducible factor (HIF) in a non-oxygen-dependent pathway

  • Yosef Laviv
  • Joshua L. Wang
  • Matthew P. Anderson
  • Ekkehard M. Kasper


Hemangioblastomas (HBs) are benign, highly vascular tumors, often characterized by loss of function of the von Hippel–Lindau (vHL) gene. They are the most common central nervous system tumor observed in vHL syndrome. Loss of function of the vHL gene creates a “pseudo-hypoxic” state, causing overactivation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-related pathways. In some cases, HBs can rapidly increase in size during pregnancy to then present acutely, which most frequently occurs after the 20th gestational week. These changes in size usually occur from enlargement of the cystic component of the HB. Due to their preferred location in the posterior fossa near critical structures as well as along the spinal cord, such cases can present with severe neurological deficits, requiring urgent surgical intervention in a multidisciplinary setting. However, the reasons for this acute flare-up during pregnancy remain poorly understood, as are the reasons why this occurs in only a subset of tumors. Unveiling the etiology for this clinical scenario can affect the treatment of HBs, as it will contribute to the understanding of the pathophysiology of such a transformation from a quiescent lesion to a symptomatic one, not only in the setting of pregnancy. Identifying the correct triggers and the conditions initiating and mediating this switch will enable us to develop preventive medications which should allow us to keep the tumor in its quiescent phase. In this pathophysiological review, we investigate the association between HB growth and pregnancy based on an analysis > 40 such published cases. We suggest that the proangiogenic state of pregnancy is the leading etiology for this striking association, and to support the argument, we discuss its potential impact on HIF overexpression in a non-hypoxic manner through activation of the PI3K/Akt/mTOR pathway by proangiogenic factors. Specifically, we discuss the involvement of placental growth factor (PlGF) and its receptor vascular endothelial growth factor receptor 1 (VEGFR-1) in various pathologic processes that can lead to the formation and growth of peritumoral edema and cysts, which are the primary causes for the development of any symptoms in HB. Both PlGF and VEGFR-1 are expressed at increased levels during pregnancy, and both have been reported as part of various pathological processes, including angiogenesis and tumorigenesis. The unique feature that both do essentially not show any significant negative impact on regular physiological processes makes them attractive therapeutic targets since very little side effects are expected. Further research into the effects of anti-PlGF or anti-VEGFR-1 therapy in HB is therefore recommended.


Hemangioblastoma Pregnancy Angiogenesis Vascular permeability Placental growth factor 


Funding information

This work was not funded or financially supported.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Beth Israel Deaconess Medical Center and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


  1. 1.
    Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, Walsh K, Aird WC (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24:294–300PubMedCrossRefGoogle Scholar
  2. 2.
    Akrami H, Mahmoodi F, Havasi S, Sharifi A (2016) PlGF knockdown inhibited tumor survival and migration in gastric cancer cell via PI3K/Akt and p38MAPK pathways. Cell Biochem Funct 34:173–180. PubMedCrossRefGoogle Scholar
  3. 3.
    Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464PubMedCrossRefGoogle Scholar
  4. 4.
    Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ (2010) Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension 56:1003–1008. PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    An J, Rettig MB (2005) Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol Cell Biol 25:7546–7556PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Autiero M, Luttun A, Tjwa M, Carmeliet P (2003) Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1:1356–1370PubMedCrossRefGoogle Scholar
  7. 7.
    Baggenstos MA, Butman JA, Oldfield EH, Lonser RR (2007) Role of edema in peritumoral cyst formation. Neurosurg Focus 22:E9PubMedCrossRefGoogle Scholar
  8. 8.
    Baker PN, Krasnow J, Roberts JM, Yeo KT (1995) Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol 86:815–821PubMedCrossRefGoogle Scholar
  9. 9.
    Bellik L, Vinci MC, Filippi S, Ledda F, Parenti A (2005) Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia. Br J Pharmacol 146:568–575PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Binder NK, Evans J, Salamonsen LA, Gardner DK, Kaitu’u-Lino TJ, Hannan NJ (2016) Placental growth factor is secreted by the human endometrium and has potential important functions during embryo development and implantation. PLoS One 11:e0163096. PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Blakeley JO, Ye X, Duda DG, Halpin CF, Bergner AL, Muzikansky A, Merker VL, Gerstner ER, Fayad LM, Ahlawat S, Jacobs MA, Jain RK, Zalewski C, Dombi E, Widemann BC, Plotkin SR (2016) Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol 34(14):1669–1675Google Scholar
  12. 12.
    Bobic S, Seys S, De Vooght V, Callebaut I, Hox V, Dooms C, Vinckier S, Jonckx B, Saint-Remy JM, Stassen JM, Bullens DM, Ceuppens JL, Carmeliet P, Hellings PW (2012) Placental growth factor contributes to bronchial neutrophilic inflammation and edema in allergic asthma. Am J Respir Cell Mol Biol 46:781–789. PubMedCrossRefGoogle Scholar
  13. 13.
    Bohling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M (1996) Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol 55:522–527PubMedCrossRefGoogle Scholar
  14. 14.
    Boker A, Ong BY (2001) Anesthesia for Cesarean section and posterior fossa craniotomy in a patient with von Hippel-Lindau disease. Can J Anaesth 48:387–390PubMedCrossRefGoogle Scholar
  15. 15.
    Bourdillon PJ, Hickman RC (1967) Von Hippel-Lindau’s disease presenting at an early age. J Neurol Neurosurg Psychiatry 30:559–562PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Broager B (1949) Multiple cerebellar angioreticulomas; discussion of high protein contents of the cysts and of enclosed parts of the subarachnoid space. Acta Psychiatr Neurol 24:317–332PubMedCrossRefGoogle Scholar
  17. 17.
    Brown MA, Zammit VC, Lowe SA (1989) Capillary permeability and extracellular fluid volumes in pregnancy-induced hypertension. Clin Sci (Lond) 77:599–604CrossRefGoogle Scholar
  18. 18.
    Cao Y, Linden P, Shima D, Browne F, Folkman J (1996) In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest 98:2507–2511PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Capone F, Profice P, Pilato F, Zollino M, Colosimo C, Di Lazzaro V (2013) Spinal hemangioblastoma presenting with low back pain in pregnancy. Spine J 13:e27–e29. PubMedCrossRefGoogle Scholar
  20. 20.
    Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395PubMedCrossRefGoogle Scholar
  21. 21.
    Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, VandenDriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583PubMedCrossRefGoogle Scholar
  22. 22.
    Carnevale D, Lembo G (2012) Placental growth factor and cardiac inflammation. Trends Cardiovasc Med 22:209–212. PubMedCrossRefGoogle Scholar
  23. 23.
    Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, Goncalves L, Gomez R, Edwin S, Mazor M (2005) Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 17:3–18PubMedCrossRefGoogle Scholar
  24. 24.
    Cianfarani F, Zambruno G, Brogelli L, Sera F, Lacal PM, Pesce M, Capogrossi MC, Failla CM, Napolitano M, Odorisio T (2006) Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential. Am J Pathol 169:1167–1182PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cipolla MJ (2007) Cerebrovascular function in pregnancy and eclampsia. Hypertension 50:14–24PubMedCrossRefGoogle Scholar
  26. 26.
    Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127. PubMedCrossRefGoogle Scholar
  27. 27.
    Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D (2001) Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery 48:55–62 discussion 62-53 PubMedGoogle Scholar
  29. 29.
    Criscuolo GR (1993) The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66:277–314PubMedPubMedCentralGoogle Scholar
  30. 30.
    De Falco S (2012) The discovery of placenta growth factor and its biological activity. Exp Mol Med 44:1–9. PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Delisle MF, Valimohamed F, Money D, Douglas MJ (2000) Central nervous system complications of von Hippel-Lindau disease and pregnancy; perinatal considerations: case report and literature review. J Matern Fetal Med 9:242–247PubMedCrossRefGoogle Scholar
  32. 32.
    Dery MA, Michaud MD, Richard DE (2005) Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37:535–540PubMedCrossRefGoogle Scholar
  33. 33.
    Donnini S, Machein MR, Plate KH, Weich HA (1999) Expression and localization of placenta growth factor and PlGF receptors in human meningiomas. J Pathol 189:66–71PubMedCrossRefGoogle Scholar
  34. 34.
    Dupperat B (1945) Tumeurs cerebrales et grossesse. Pr Med 52:118Google Scholar
  35. 35.
    Erdogan B, Sen O, Aydin MV, Bagis T, Bavbek M (2002) Cerebellar hemangioblastoma in pregnancy. A case report. J Reprod Med 47:864–866PubMedGoogle Scholar
  36. 36.
    Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111PubMedCrossRefGoogle Scholar
  37. 37.
    Evans P, Wheeler T, Anthony F, Osmond C (1997) Maternal serum vascular endothelial growth factor during early pregnancy. Clin Sci (Lond) 92:567–571CrossRefGoogle Scholar
  38. 38.
    Evans PW, Wheeler T, Anthony FW, Osmond C (1998) A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod 13:1057–1062PubMedCrossRefGoogle Scholar
  39. 39.
    Feldman MJ, Sizdahkhani S, Edwards NA, Merrill MJ, Ray-Chaudhury A, Zhuang Z, Lonser RR, Oldfield EH, Chittiboina P (2016) Loss of quiescence in von Hippel-Lindau hemangioblastomas is associated with erythropoietin signaling. Sci Rep 6:35486Google Scholar
  40. 40.
    Ferrante L, Celli P, Fraioli B, Santoro A (1984) Haemangioblastomas of the posterior cranial fossa. Acta Neurochir 71:283–294PubMedCrossRefGoogle Scholar
  41. 41.
    Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475PubMedCrossRefGoogle Scholar
  42. 42.
    Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956. PubMedCrossRefGoogle Scholar
  43. 43.
    Frantzen C, Kruizinga RC, van Asselt SJ, Zonnenberg BA, Lenders JW, de Herder WW, Walenkamp AM, Giles RH, Hes FJ, Sluiter WJ, van Pampus MG, Links TP (2012) Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology 79:793–796PubMedCrossRefGoogle Scholar
  44. 44.
    Ghosh S, Tergaonkar V, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T (2006) Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 10:215–226PubMedCrossRefGoogle Scholar
  45. 45.
    Glasker S, Vortmeyer AO, Lonser RR, Lubensky IA, Okamoto H, Xia JB, Li J, Milne E, Kowalak JA, Oldfield EH, Zhuang Z (2006) Proteomic analysis of hemangioblastoma cyst fluid. Cancer Biol Ther 5:549–553PubMedCrossRefGoogle Scholar
  46. 46.
    Green CJ, Lichtlen P, Huynh NT, Yanovsky M, Laderoute KR, Schaffner W, Murphy BJ (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61:2696–2703PubMedGoogle Scholar
  47. 47.
    Grimbert P, Chauveau D, Remy SR, Grunfeld JP (1999) Pregnancy in von Hippel-Lindau disease. Am J Obstet Gynecol 180:110–111PubMedCrossRefGoogle Scholar
  48. 48.
    Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hallsworth D, Thompson J, Wilkinson D, Kerr RS, Russell R (2015) Intracranial pressure monitoring and caesarean section in a patient with von Hippel-Lindau disease and symptomatic cerebellar haemangioblastomas. Int J Obstet Anesth 24:73–77PubMedCrossRefGoogle Scholar
  50. 50.
    Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849PubMedPubMedCentralGoogle Scholar
  51. 51.
    Hatva E, Bohling T, Jaaskelainen J, Persico MG, Haltia M, Alitalo K (1996) Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 148:763–775PubMedPubMedCentralGoogle Scholar
  52. 52.
    Hayashi S, Takeda N, Komura E (2010) Symptomatic cerebellar hemorrhage from recurrent hemangioblastoma during delivery. Case report. Neurol Med Chir (Tokyo) 50:1105–1107CrossRefGoogle Scholar
  53. 53.
    Hayden MG, Gephart R, Kalanithi P, Chou D (2009) Von Hippel-Lindau disease in pregnancy: a brief review. J Clin Neurosci 16:611–613. PubMedCrossRefGoogle Scholar
  54. 54.
    Hiratsuka S, Kataoka Y, Nakao K, Nakamura K, Morikawa S, Tanaka S, Katsuki M, Maru Y, Shibuya M (2005) Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos. Mol Cell Biol 25:355–363PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213PubMedGoogle Scholar
  56. 56.
    Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95:9349–9354PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ho MC, Chen CN, Lee H, Hsieh FJ, Shun CT, Chang CL, Lai YT, Lee PH (2007) Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma. Cancer Lett 250:237–249PubMedCrossRefGoogle Scholar
  58. 58.
    Hoeve JV (1923) Eye diseases in tuberous sclerosis of the brain and in Recklinghausen’s disease. Trans Ophthalmol Soc U K 43:534–541Google Scholar
  59. 59.
    Hrisomalos FN, Maturi RK, Pata V (2010) Long-term use of intravitreal bevacizumab (avastin) for the treatment of von hippel-lindau associated retinal hemangioblastomas. Open Ophthalmol J 4:66–69PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Ilhan-Mutlu A, Wagner L, Widhalm G, Wohrer A, Bartsch S, Czech T, Heinzl H, Leutmezer F, Prayer D, Marosi C, Base W, Preusser M (2013) Exploratory investigation of eight circulating plasma markers in brain tumor patients. Neurosurg Rev 36:45–55; discussion 55-46. PubMedCrossRefGoogle Scholar
  61. 61.
    Incio J, Tam J, Rahbari NN, Suboj P, McManus DT, Chin SM, Vardam TD, Batista A, Babykutty S, Jung K, Khachatryan A, Hato T, Ligibel JA, Krop IE, Puchner SB, Schlett CL, Hoffmman U, Ancukiewicz M, Shibuya M, Carmeliet P, Soares R, Duda DG, Jain RK, Fukumura D (2016) PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin Cancer Res 22:2993–3004. PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Inoue A, Kohno S, Kumon Y, Watanabe H, Ohnishi T, Hashimoto H, Matsubara K (2015) A case of cerebellar hemangioblastoma complicated by pregnancy and concerns about the surgical period. No Shinkei Geka 43:57–62PubMedGoogle Scholar
  63. 63.
    Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH (2008) Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 108:210–222. PubMedCrossRefGoogle Scholar
  64. 64.
    Jeffreys R (1975) Clinical and surgical aspects of posterior fossa haemangioblastomata. J Neurol Neurosurg Psychiatry 38:105–111PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T, Yao M (1994) Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54:4845–4847PubMedGoogle Scholar
  66. 66.
    Kasarskis EJ, Tibbs PA, Lee C (1988) Cerebellar hemangioblastoma symptomatic during pregnancy. Neurosurgery 22:770–772PubMedCrossRefGoogle Scholar
  67. 67.
    Kenyon AP, Haider S, Ashkan K, Nelson-Piercy C (2009) Cerebellar haemangioblastoma presenting with dizziness in pregnancy: case report and review of the literature. Obstet Med 2:164–167. PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Kim KJ, Cho CS, Kim WU (2012) Role of placenta growth factor in cancer and inflammation. Exp Mol Med 44:10–19. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Korula G, Farling P (1998) Anesthetic management for a combined Cesarean section and posterior fossa craniectomy. J Neurosurg Anesthesiol 10:30–33PubMedCrossRefGoogle Scholar
  71. 71.
    Krauss T, Pauer HU, Augustin HG (2004) Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 23:101–111PubMedCrossRefGoogle Scholar
  72. 72.
    Kuhnigk H, Danhauser-Leistner I (1994) Cesarean section with subsequent craniotomy in the area of the posterior cranial fossa. Anasthesiol Intensivmed Notfallmed Schmerzther 29:184–187PubMedCrossRefGoogle Scholar
  73. 73.
    Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, Gull I, Lessing JB (1997) Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 38:302–306PubMedCrossRefGoogle Scholar
  74. 74.
    Kurne A, Bakar B, Arsava EM, Tan E (2003) Pregnancy associated quadriparesis in a patient with Von-Hippel Lindau disease. J Neurol 250:234–235PubMedCrossRefGoogle Scholar
  75. 75.
    Landgren E, Schiller P, Cao Y, Claesson-Welsh L (1998) Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 16:359–367PubMedCrossRefGoogle Scholar
  76. 76.
    Lassen U, Nielsen DL, Sorensen M, Winstedt L, Niskanen T, Stenberg Y, Pakola S, Stassen JM, Glazer S (2012) A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours. Br J Cancer 106:678–684. PubMedPubMedCentralGoogle Scholar
  77. 77.
    Laviv Y, Kasper BS, Kasper EM (2017) Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels, CSF clotting, and communicating hydrocephalus: a comprehensive review. Neurosurg Rev 7:017–0839Google Scholar
  78. 78.
    Lechowski S, Stypula J, Niespodzianski K, Domagala S (1992) Surgery of brain angioma (hemangioblastoma cerebelli) during the 31st week of pregnancy. Ginekol Pol 63:424–427PubMedGoogle Scholar
  79. 79.
    Lee JY, Dong SM, Park WS, Yoo NJ, Kim CS, Jang JJ, Chi JG, Zbar B, Lubensky IA, Linehan WM, Vortmeyer AO, Zhuang Z (1998) Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 58:504–508PubMedGoogle Scholar
  80. 80.
    Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005PubMedCrossRefGoogle Scholar
  81. 81.
    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 (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683PubMedCrossRefGoogle Scholar
  82. 82.
    Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, Blink AL, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2005) Urinary placental growth factor and risk of preeclampsia. JAMA 293:77–85PubMedCrossRefGoogle Scholar
  83. 83.
    Lindau A (1931) Discussion on vascular tumours of the brain and spinal cord: Joint Discussion No. 1. Proc R Soc Med 24:363–388Google Scholar
  84. 84.
    List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bellamy W, Powis G (2004) Vascular endothelial growth factor receptor-1 and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid leukemia cells. Exp Hematol 32:526–535PubMedCrossRefGoogle Scholar
  85. 85.
    Luttun A, Tjwa M, Carmeliet P (2002) Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann N Y Acad Sci 979:80–93PubMedCrossRefGoogle Scholar
  86. 86.
    Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840PubMedGoogle Scholar
  87. 87.
    Lyall F, Greer IA, Boswell F, Fleming R (1997) Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol 104:223–228PubMedCrossRefGoogle Scholar
  88. 88.
    Mӧller H (1944) Ophthalmic symptoms and heredity in cerebellar angioreticuloma. Acta Psychiatr Neurol 19:275–292CrossRefGoogle Scholar
  89. 89.
    Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 88:9267–9271PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Matsumoto K, Suzuki K, Koike H, Okamura K, Tsuchiya K, Uchida T, Takezawa Y, Kobayashi M, Yamanaka H (2003) Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels. Anticancer Res 23:4953–4958PubMedGoogle Scholar
  91. 91.
    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 (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Morii K, Tanaka R, Washiyama K, Kumanishi T, Kuwano R (1993) Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem Biophys Res Commun 194:749–755PubMedCrossRefGoogle Scholar
  93. 93.
    Muramatsu M, Yamamoto S, Osawa T, Shibuya M (2010) Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res 70:8211–8221. PubMedCrossRefGoogle Scholar
  94. 94.
    Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109–119. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Naidoo K, Bhigjee AI (1998) Multiple cerebellar haemangioblastomas symptomatic during pregnancy. Br J Neurosurg 12:281–284PubMedCrossRefGoogle Scholar
  96. 96.
    Nathan L, Satin AJ, Twickler DM (1995) Cerebellar hemangioblastoma complicating pregnancy. A case report. J Reprod Med 40:662–664PubMedGoogle Scholar
  97. 97.
    Newell LF, Holtan SG (2017) Placental growth factor: what hematologists need to know. Blood Rev 31:57–62. PubMedCrossRefGoogle Scholar
  98. 98.
    Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H (1998) Placenta growth factor (PlGF) mRNA expression in brain tumors. J Neuro-Oncol 40:123–130CrossRefGoogle Scholar
  99. 99.
    Odorisio T, Cianfarani F, Failla CM, Zambruno G (2006) The placenta growth factor in skin angiogenesis. J Dermatol Sci 41:11–19PubMedCrossRefGoogle Scholar
  100. 100.
    Ogasawara KK, Ogasawara EM, Hirata G (1995) Pregnancy complicated by von Hippel-Lindau disease. Obstet Gynecol 85:829–831PubMedCrossRefGoogle Scholar
  101. 101.
    Omar AI (2012) Bevacizumab for the treatment of surgically unresectable cervical cord hemangioblastoma: a case report. J Med Case Rep 6:1752–1947Google Scholar
  102. 102.
    Ortega-Martinez M, Cabezudo JM, Fernandez-Portales I, Pineda-Palomo M, Rodriguez-Sanchez JA, Bernal-Garcia LM (2007) Multiple filum terminale hemangioblastomas symptomatic during pregnancy. Case report. J Neurosurg Spine 7:254–258PubMedCrossRefGoogle Scholar
  103. 103.
    Othmane IS, Shields C, Singh A, Shields J, Goldman W (1999) Postpartum cerebellar herniation in von Hippel-Lindau syndrome. Am J Ophthalmol 128:387–389PubMedCrossRefGoogle Scholar
  104. 104.
    Palm M, Basu S, Larsson A, Wernroth L, Akerud H, Axelsson O (2011) A longitudinal study of plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), sFlt1: PlGF ratio and vascular endothelial growth factor (VEGF-A) in normal pregnancy. Acta Obstet Gynecol Scand 90:1244–1251. PubMedCrossRefGoogle Scholar
  105. 105.
    Palmer JJ (1972) Haemangioblastomas. A review of 81 cases. Acta Neurochir 27:125–148PubMedCrossRefGoogle Scholar
  106. 106.
    Park DM, Zhuang Z, Chen L, Szerlip N, Maric I, Li J, Sohn T, Kim SH, Lubensky IA, Vortmeyer AO, Rodgers GP, Oldfield EH, Lonser RR (2007) von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med 4:e60PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654PubMedGoogle Scholar
  108. 108.
    Pereda Rios A, Pintado Recarte P, De Leon-Luis J, Fernandez-Garcia P, Iza B, Salinero Paniagua E, Aguaron de la Cruz A, Ortiz Quintana L (2012) Cerebellar hemangioblastoma as the cause of maternal obstructive hydrocephalus during the third trimester. Eur J Obstet Gynecol Reprod Biol 165:370–372PubMedCrossRefGoogle Scholar
  109. 109.
    Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, Kalra VK, Malik P (2003) Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 102:1506–1514PubMedCrossRefGoogle Scholar
  110. 110.
    Persico MG, Vincenti V, DiPalma T (1999) Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr Top Microbiol Immunol 237:31–40PubMedGoogle Scholar
  111. 111.
    Pierscianek D, Wolf S, Keyvani K, El Hindy N, Stein KP, Sandalcioglu IE, Sure U, Mueller O, Zhu Y (2017) Study of angiogenic signaling pathways in hemangioblastoma. Neuropathology 37:3–11. Epub 12016 Jul 12317
  112. 112.
    Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MA, Heissig B, Hattori K (2003) Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann N Y Acad Sci 996:49–60PubMedCrossRefGoogle Scholar
  113. 113.
    Rehman T, Ali R, Yonas H (2009) Cerebellar haemangioblastoma: temporising treatment in a high risk pregnancy. BMJ Case Rep.
  114. 114.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674PubMedCrossRefGoogle Scholar
  115. 115.
    Robinson RG (1966) Aspects of the natural history of cerebellar haemangioblastomas. Acta Neurol Scand 41:372–380PubMedCrossRefGoogle Scholar
  116. 116.
    Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44. Epub 2011 Jan 1016
  117. 117.
    Romansky K, Arnaudova V, Nachev S (1992) Hemangioblastoma during pregnancy. Case report. Zentralbl Neurochir 53:37–39PubMedGoogle Scholar
  118. 118.
    Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karumanchi SA (2008) A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med 21:9–23. PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Sabin FR (2002) Preliminary note on the differentiation of angioblasts and the method by which they produce blood-vessels, blood-plasma and red blood-cells as seen in the living chick. 1917. J Hematother Stem Cell Res 11:5–7PubMedCrossRefGoogle Scholar
  120. 120.
    Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66:11432–11440PubMedCrossRefGoogle Scholar
  121. 121.
    Satyarthee GD, Kumar S (2016) Cerebellar hemangioblastoma symptomatic during pregnancy: a short review. Am J Clin Neurol Neurosurg 2:25–28Google Scholar
  122. 122.
    Scarcella G, Allen MB Jr, Andy OJ (1961) Vascular lesions of the posterior fossa during pregnancy. Am J Obstet Gynecol 82:836–840PubMedCrossRefGoogle Scholar
  123. 123.
    Schmidt T, Kharabi Masouleh B, Loges S, Cauwenberghs S, Fraisl P, Maes C, Jonckx B, De Keersmaecker K, Kleppe M, Tjwa M, Schenk T, Vinckier S, Fragoso R, De Mol M, Beel K, Dias S, Verfaillie C, Clark RE, Brummendorf TH, Vandenberghe P, Rafii S, Holyoake T, Hochhaus A, Cools J, Karin M, Carmeliet G, Dewerchin M, Carmeliet P (2011) Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia. Cancer Cell 19:740–753. PubMedCrossRefGoogle Scholar
  124. 124.
    Schreurs MP, Houston EM, May V, Cipolla MJ (2012) The adaptation of the blood-brain barrier to vascular endothelial growth factor and placental growth factor during pregnancy. FASEB J 26:355–362. PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Selvaraj SK, Giri RK, Perelman N, Johnson C, Malik P, Kalra VK (2003) Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood 102:1515–1524PubMedCrossRefGoogle Scholar
  126. 126.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  127. 127.
    Shankar GM, Taylor-Weiner A, Lelic N, Jones RT, Kim JC, Francis JM, Abedalthagafi M, Borges LF, Coumans JV, Curry WT, Nahed BV, Shin JH, Paek SH, Park SH, Stewart C, Lawrence MS, Cibulskis K, Thorner AR, Van Hummelen P, Stemmer-Rachamimov AO, Batchelor TT, Carter SL, Hoang MP, Santagata S, Louis DN, Barker FG, Meyerson M, Getz G, Brastianos PK, Cahill DP (2014) Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun 2:014–0167CrossRefGoogle Scholar
  128. 128.
    Sharkey AM, Cooper JC, Balmforth JR, McLaren J, Clark DE, Charnock-Jones DS, Morris NH, Smith SK (1996) Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Investig 26:1182–1185CrossRefGoogle Scholar
  129. 129.
    Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076. PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Stein AA, Schilp AO, Whitfield RD (1960) The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–761PubMedCrossRefGoogle Scholar
  131. 131.
    Takahashi A, Sasaki H, Kim SJ, Kakizoe T, Miyao N, Sugimura T, Terada M, Tsukamoto T (1999) Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. Biochem Biophys Res Commun 257:855–859PubMedCrossRefGoogle Scholar
  132. 132.
    Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Terada M (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237PubMedGoogle Scholar
  133. 133.
    Tandon V, Hiwale S, Amle D, Nagaria T, Patra PK (2017) Assessment of serum vascular endothelial growth factor levels in pregnancy-induced hypertension patients. J Pregnancy 3179670:4Google Scholar
  134. 134.
    Tarallo V, Vesci L, Capasso O, Esposito MT, Riccioni T, Pastore L, Orlandi A, Pisano C, De Falco S (2010) A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization. Cancer Res 70:1804–1813. PubMedCrossRefGoogle Scholar
  135. 135.
    Terry AR, Merker VL, Barker FG 2nd, Leffert L, Bateman BT, Souter I, Plotkin SR (2015) Pregnancy complications in women with rare tumor suppressor syndromes affecting central and peripheral nervous system. Am J Obstet Gynecol 213:108–109. PubMedCrossRefGoogle Scholar
  136. 136.
    Torry RJ, Rongish BJ (1992) Angiogenesis in the uterus: potential regulation and relation to tumor angiogenesis. Am J Reprod Immunol 27:171–179PubMedCrossRefGoogle Scholar
  137. 137.
    Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, Loges S, Albrecht I, Jonckx B, Vinckier S, Van Steenkiste C, Tugues S, Rolny C, De Mol M, Dettori D, Hainaud P, Coenegrachts L, Contreres JO, Van Bergen T, Cuervo H, Xiao WH, Le Henaff C, Buysschaert I, Kharabi Masouleh B, Geerts A, Schomber T, Bonnin P, Lambert V, Haustraete J, Zacchigna S, Rakic JM, Jimenez W, Noel A, Giacca M, Colle I, Foidart JM, Tobelem G, Morales-Ruiz M, Vilar J, Maxwell P, Vinores SA, Carmeliet G, Dewerchin M, Claesson-Welsh L, Dupuy E, Van Vlierberghe H, Christofori G, Mazzone M, Detmar M, Collen D, Carmeliet P (2010) Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141:178–190. PubMedCrossRefGoogle Scholar
  138. 138.
    Vaquero J, Martinez R (1984) Progesterone receptor proteins in cerebellar hemangioblastoma. Surg Neurol 21:99PubMedCrossRefGoogle Scholar
  139. 139.
    Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH (2004) Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol 55:721–728PubMedCrossRefGoogle Scholar
  140. 140.
    Wanebo JE, Lonser RR, Glenn GM, Oldfield EH (2003) The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 98:82–94PubMedCrossRefGoogle Scholar
  141. 141.
    Weed S, Bastek JA, Anton L, Elovitz MA, Parry S, Srinivas SK (2012) Examining the correlation between placental and serum placenta growth factor in preeclampsia. Am J Obstet Gynecol 207:140.e141–140.e146. CrossRefGoogle Scholar
  142. 142.
    Wei SC, Tsao PN, Yu SC, Shun CT, Tsai-Wu JJ, Wu CH, Su YN, Hsieh FJ, Wong JM (2005) Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 54:666–672PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Wikstrom AK, Larsson A, Eriksson UJ, Nash P, Norden-Lindeberg S, Olovsson M (2007) Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol 109:1368–1374PubMedCrossRefGoogle Scholar
  144. 144.
    Wizigmann-Voos S, Breier G, Risau W, Plate KH (1995) Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55:1358–1364PubMedGoogle Scholar
  145. 145.
    Wu Y, Hooper AT, Zhong Z, Witte L, Bohlen P, Rafii S, Hicklin DJ (2006) The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer 119:1519–1529PubMedCrossRefGoogle Scholar
  146. 146.
    Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC (2008) Elevated levels of placental growth factor represent an adaptive host response in sepsis. J Exp Med 205:2623–2631. PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V, Shibuya M, Ferrara N, Bais C (2011) Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci U S A 108:11590–11595.  10.11073/pnas.1109029108 PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Yao YG, Yang HS, Cao Z, Danielsson J, Duh EJ (2005) Upregulation of placental growth factor by vascular endothelial growth factor via a post-transcriptional mechanism. FEBS Lett 579:1227–1234PubMedCrossRefGoogle Scholar
  149. 149.
    Ye DY, Bakhtian KD, Asthagiri AR, Lonser RR (2012) Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg 117:818–824PubMedCrossRefGoogle Scholar
  150. 150.
    Yonekura H, Sakurai S, Liu X, Migita H, Wang H, Yamagishi S, Nomura M, Abedin MJ, Unoki H, Yamamoto Y, Yamamoto H (1999) Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis. J Biol Chem 274:35172–35178PubMedCrossRefGoogle Scholar
  151. 151.
    Zhang L, Chen J, Ke Y, Mansel RE, Jiang WG (2005) Expression of Placenta growth factor (PlGF) in non-small cell lung cancer (NSCLC) and the clinical and prognostic significance. World J Surg Oncol 3:68PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Zhou Y, Tu C, Zhao Y, Liu H, Zhang S (2016) Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease. Biochem Biophys Res Commun 470:967–974. PubMedCrossRefGoogle Scholar
  153. 153.
    Zhuang Z, Frerich JM, Huntoon K, Yang C, Merrill MJ, Abdullaev Z, Pack SD, Shively SB, Stamp G, Lonser RR (2014) Tumor derived vasculogenesis in von Hippel-Lindau disease-associated tumors. Sci Rep 4:4102Google Scholar
  154. 154.
    Ziche M, Maglione D, Ribatti D, Morbidelli L, Lago CT, Battisti M, Paoletti I, Barra A, Tucci M, Parise G, Vincenti V, Granger HJ, Viglietto G, Persico MG (1997) Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Lab Investig 76:517–531PubMedGoogle Scholar
  155. 155.
    Zilidis G, Cadoux-Hudson TA (2007) Recurrent dural based cystic cerebellar haemangioblastoma in a patient with von Hippel-Lindau disease. Acta Neurochir 149:433–436PubMedCrossRefGoogle Scholar
  156. 156.
    Zygmunt M, Herr F, Munstedt K, Lang U, Liang OD (2003) Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 22:S10–S18CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Division of Surgery, Department of Neurosurgery, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations