Volume 83, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Lymphatic dilatation, dysfunction, and lymphangiogenesis are hallmarks of patent lymphatic filariasis, observed even in those with subclinical microfilaremia, through processes associated, in part, by vascular endothelial growth factors (VEGFs). A panel of pro-angiogenic factors was measured in the plasma of subjects from filaria-endemic regions using multiplexed immunological assays. Compared with endemic normal control subjects, those with both subclinical microfilaremia, and those with longstanding lymphedema had significantly elevated levels of VEGF-A, VEGF-C, VEGF-D, and angiopoeitins (Ang-1/Ang-2), with only levels of basic fibroblast growth factor (bFGF) and placental growth factor (PlGF) being elevated only if lymphedema was evident. Furthermore, levels of these factors 1-year post-treatment with doxycycline were similar to pretreatment levels suggesting a minimal role, if any, for . Our data support the concept that filarial infection is associated with elevated levels of most of the known pro-angiogenic factors, with only a few being associated with the serious pathologic consequences associated with infection.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Alitalo K, Tammela T, Petrova TV, , 2005. Lymphangiogenesis in development and human disease. Nature 438: 946953.[Crossref] [Google Scholar]
  2. Klei TR, Enright FM, Blanchard DP, Uhl SA, , 1981. Specific hypo-responsive granulomatous tissue reactions in Brugia pahangi-infected birds. Acta Trop 38: 267276. [Google Scholar]
  3. Nutman TB, Kumaraswami V, Pao L, Narayanan PR, Ottesen EA, , 1987. An analysis of in vitro B cell immune responsiveness in human lymphatic filariasis. J Immunol 138: 39543959. [Google Scholar]
  4. Ottesen EA, , 1980. Immunopathology of lymphatic filariasis in man. Springer Semin Immunopathol 2: 373385.[Crossref] [Google Scholar]
  5. Piessens WF, McGreevy PB, Piessens PW, McGreevy M, Koiman I, Saroso JS, Dennis DT, , 1980. Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens. J Clin Invest 65: 172179.[Crossref] [Google Scholar]
  6. Ristimaki A, Narko K, Enholm B, Joukov V, Alitalo K, , 1998. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem 273: 84138418.[Crossref] [Google Scholar]
  7. Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A, , 2006. Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2: e92.[Crossref] [Google Scholar]
  8. Bennuru S, Nutman TB, , 2009. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis. PLoS Pathog 5: e1000688.[Crossref] [Google Scholar]
  9. Gopinath R, Hanna LE, Kumaraswami V, Perumal V, Kavitha V, Vijayasekaran V, Nutman TB, , 2000. Perturbations in eosinophil homeostasis following treatment of lymphatic filariasis. Infect Immun 68: 9399.[Crossref] [Google Scholar]
  10. Coulibaly YI, Dembele B, Diallo AA, Lipner EM, Doumbia SS, Coulibaly SY, Konate S, Diallo DA, Yalcouye D, Kubofcik J, Doumbo OK, Traore AK, Keita AD, Fay MP, Traore SF, Nutman TB, Klion AD, , 2009. A randomized trial of doxycycline for Mansonella perstans infection. N Engl J Med 361: 14481458.[Crossref] [Google Scholar]
  11. Augustin HG, Koh GY, Thurston G, Alitalo K, , 2009. Control of vascular morphogenesis and homeostasis through the angiopoietin-tie system. Nat Rev Mol Cell Biol 10: 165177.[Crossref] [Google Scholar]
  12. Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, Hawkes M, Krudsood S, Looareesuwan S, John CC, Liles WC, Kain KC, , 2009. Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS ONE 4: e4912.[Crossref] [Google Scholar]
  13. Shantha Kumara HM, Hoffman A, Kim IY, Feingold D, Dujovny N, Kalady M, Luchtefeld M, Whelan RL, , 2009. Colorectal resection, both open and laparoscopic-assisted, in patients with benign indications is associated with proangiogenic changes in plasma angiopoietin 1 and 2 levels. Surg Endosc 23: 409415.[Crossref] [Google Scholar]
  14. Debrah AY, Mand S, Toliat MR, Marfo-Debrekyei Y, Batsa L, Nurnberg P, Lawson B, Adjei O, Hoerauf A, Pfarr K, , 2007. Plasma vascular endothelial growth Factor-A (VEGF-A) and VEGF-A gene polymorphism are associated with hydrocele development in lymphatic filariasis. Am J Trop Med Hyg 77: 601608. [Google Scholar]
  15. Esterre P, Plichart C, Huin-Blondey MO, Nguyen LN, , 2005. Soluble cellular adhesion molecules, selectins, VEGF and endothelin-1 in patients with Wuchereria bancrofti infection and association with clinical status. Parasite Immunol 27: 916.[Crossref] [Google Scholar]
  16. Karpanen T, Alitalo K, , 2008. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3: 367397.[Crossref] [Google Scholar]
  17. Bruno E, Cooper RJ, Wilson EL, Gabrilove JL, Hoffman R, , 1993. Basic fibroblast growth factor promotes the proliferation of human megakaryocyte progenitor cells. Blood 82: 430435. [Google Scholar]
  18. Wilson EL, Rifkin DB, Kelly F, Hannocks MJ, Gabrilove JL, , 1991. Basic fibroblast growth factor stimulates myelopoiesis in long-term human bone marrow cultures. Blood 77: 954960. [Google Scholar]
  19. Mandriota SJ, Pepper MS, , 1997. Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci 110: 22932302. [Google Scholar]
  20. Hasebe T, Imoto S, Ogura T, Mukai K, , 1997. Significance of basic fibroblast growth factor and fibroblast growth factor receptor protein expression in the formation of fibrotic focus in invasive ductal carcinoma of the breast. Jpn J Cancer Res 88: 877885.[Crossref] [Google Scholar]
  21. Ohshima K, Sugihara M, Suzumiya J, Haraoka S, Kanda M, Shimazaki K, Katoh K, Kumagawa M, Kikuchi M, , 1999. Basic fibroblast growth factor and fibrosis in Hodgkin's disease. Pathol Res Pract 195: 149155.[Crossref] [Google Scholar]
  22. Ebos JM, Lee CR, Bogdanovic E, Alami J, Van Slyke P, Francia G, Xu P, Mutsaers AJ, Dumont DJ, Kerbel RS, , 2008. Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res 68: 521529.[Crossref] [Google Scholar]
  23. Herold-Mende C, Steiner HH, Andl T, Riede D, Buttler A, Reisser C, Fusenig NE, Mueller MM, , 1999. Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. Lab Invest 79: 15731582. [Google Scholar]
  24. Pallares J, Rojo F, Iriarte J, Morote J, Armadans LI, de Torres I, , 2006. Study of microvessel density and the expression of the angiogenic factors VEGF, bFGF and the receptors Flt-1 and FLK-1 in benign, premalignant and malignant prostate tissues. Histol Histopathol 21: 857865. [Google Scholar]
  25. Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E, , 2006. Circulating serum levels of angiogenic factors and vascular endothelial growth factor receptors 1 and 2 in melanoma patients. Melanoma Res 16: 405411.[Crossref] [Google Scholar]
  26. Hu Q, Dey AL, Yang Y, Shen Y, Jilani IB, Estey EH, Kantarjian HM, Giles FJ, Albitar M, , 2004. Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes. Cancer 100: 18841891.[Crossref] [Google Scholar]
  27. Faderl S, Do KA, Johnson MM, Keating M, O'Brien S, Jilani I, Ferrajoli A, Ravandi-Kashani F, Aguilar C, Dey A, Thomas DA, Giles FJ, Kantarjian HM, Albitar M, , 2005. Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia. Blood 106: 43034307.[Crossref] [Google Scholar]
  28. Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, Kalayanarooj S, Libraty DH, Green S, Ennis FA, Rothman AL, , 2007. Virus-induced decline in soluble vascular endothelial growth receptor 2 is associated with plasma leakage in dengue hemorrhagic fever. J Virol 81: 15921600.[Crossref] [Google Scholar]
  29. Tseng JJ, Chou MM, Hsieh YT, Wen MC, Ho ES, Hsu SL, , 2006. Differential expression of vascular endothelial growth factor, placenta growth factor and their receptors in placentae from pregnancies complicated by placenta accreta. Placenta 27: 7078.[Crossref] [Google Scholar]
  30. Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ, , 2007. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5: 32.[Crossref] [Google Scholar]
  31. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB, , 2008. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26: 47084713.[Crossref] [Google Scholar]
  32. Strumberg D, Schultheis B, Adamietz IA, Christensen O, Buechert M, Kraetzschmar J, Rajagopalan P, Ludwig M, Frost A, Steinbild S, Scheulen ME, Mross K, , 2008. Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Cancer 99: 15791585.[Crossref] [Google Scholar]
  33. Kendall RL, Thomas KA, , 1993. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90: 1070510709.[Crossref] [Google Scholar]
  34. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM, , 1999. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286: 25112514.[Crossref] [Google Scholar]
  35. Papapetropoulos A, Garcia-Cardena G, Dengler TJ, Maisonpierre PC, Yancopoulos GD, Sessa WC, , 1999. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab Invest 79: 213223. [Google Scholar]
  36. Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A, , 2003. Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production. Br J Pharmacol 139: 329336.[Crossref] [Google Scholar]
  37. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ, , 1999. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284: 19941998.[Crossref] [Google Scholar]
  38. Fainaru O, Adini I, Benny O, Bazinet L, Pravda E, D'Amato R, Folkman J, , 2008. Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. FASEB J 22: 37283735.[Crossref] [Google Scholar]
  39. Eberhard ML, Hightower AW, Addiss DG, Lammie PJ, , 1997. Clearance of Wuchereria bancrofti antigen after treatment with diethylcarbamazine or ivermectin. Am J Trop Med Hyg 57: 483486. [Google Scholar]
  40. Ismail MM, Jayakody RL, Weil GJ, Nirmalan N, Jayasinghe KS, Abeyewickrema W, Rezvi Sheriff MH, Rajaratnam HN, Amarasekera N, de Silva DC, Michalski ML, Dissanaike AS, , 1998. Efficacy of single dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of bancroftian filariasis. Trans R Soc Trop Med Hyg 92: 9497.[Crossref] [Google Scholar]
  41. Nicolas L, Plichart C, Nguyen LN, Moulia-Pelat JP, , 1997. Reduction of Wuchereria bancrofti adult worm circulating antigen after annual treatments of diethylcarbamazine combined with ivermectin in French Polynesia. J Infect Dis 175: 489492.[Crossref] [Google Scholar]
  42. Weil GJ, Ramzy RM, El Setouhy M, Kandil AM, Ahmed ES, Faris R, , 1999. A longitudinal study of Bancroftian filariasis in the Nile Delta of Egypt: baseline data and one-year follow-up. Am J Trop Med Hyg 61: 5358. [Google Scholar]
  43. Weil GJ, Sethumadhavan KV, Santhanam S, Jain DC, Ghosh TK, , 1988. Persistence of parasite antigenemia following diethylcarbamazine therapy of bancroftian filariasis. Am J Trop Med Hyg 38: 589595. [Google Scholar]
  44. Dreyer G, Addiss D, Williamson J, Noroes J, , 2006. Efficacy of co-administered diethylcarbamazine and albendazole against adult Wuchereria bancrofti . Trans R Soc Trop Med Hyg 100: 11181125.[Crossref] [Google Scholar]
  45. Hussein O, El Setouhy M, Ahmed ES, Kandil AM, Ramzy RM, Helmy H, Weil GJ, , 2004. Duplex Doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in Bancroftian filariasis. Am J Trop Med Hyg 71: 471477. [Google Scholar]
  46. Noroes J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D, , 1997. Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo . Trans R Soc Trop Med Hyg 91: 7881.[Crossref] [Google Scholar]
  47. Ottesen EA, Duke BO, Karam M, Behbehani K, , 1997. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ 75: 491503. [Google Scholar]
  48. Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Buttner M, Adjei O, Buttner D, Hoerauf A, , 2007. Macrofilaricidal effect of 4 weeks of treatment with doxycycline on Wuchereria bancrofti . Trop Med Int Health 12: 14331441.[Crossref] [Google Scholar]
  49. Bennuru S, Semnani R, Meng Z, Ribeiro JM, Veenstra TD, Nutman TB, , 2009. Brugia malayi excreted/secreted proteins at the host/parasite interface: stage- and gender-specific proteomic profiling. PLoS Negl Trop Dis 3: e410.[Crossref] [Google Scholar]
  50. Hewitson JP, Harcus YM, Curwen RS, Dowle AA, Atmadja AK, Ashton PD, Wilson A, Maizels RM, , 2008. The secretome of the filarial parasite, Brugia malayi: proteomic profile of adult excretory-secretory products. Mol Biochem Parasitol 160: 821.[Crossref] [Google Scholar]
  51. Moreno Y, Geary TG, , 2008. Stage- and gender-specific proteomic analysis of Brugia malayi excretory-secretory products. PLoS Negl Trop Dis 2: e326.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 20 Jan 2010
  • Accepted : 08 Jun 2010
  • Published online : 05 Oct 2010

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error