title: Induction of the vascular endothelial growth factor pathway in the brain of adults with fatal falciparum malaria is a non-specific response to severe disease.
abstract: OBJECTIVE
  Pathological or neuroprotective mechanisms in the brain in severe malaria may arise from microvascular obstruction with malaria-parasitized erythrocytes. This study aimed to investigate the role of hypoxia and induction of the vascular endothelial growth factor (VEGF) pathway in the neuropathophysiology of severe malaria.
  
  
  RESULTS
  Immunohistochemistry was performed on post mortem brain tissue sections from 20 cases of severe malaria and examined for the expression of transcriptional regulators of VEGF [hypoxia-inducible factor-1 alpha (HIF-1alpha), HIF-2alpha], DEC-1, VEGF, VEGF receptors 1 and 2, and the activated, phosphorylated VEGF receptor 2 (pKDR). HIFs showed limited protein expression and/or translocation to cell nuclei in severe malaria, but DEC-1, which is more stable and regulated by HIF-1alpha, was observed. There was heterogeneous expression of VEGF and its receptors in severe malaria and non-malarial disease controls. pKDR expression on vessels was greater in malaria cases than in controls but did not correlate with parasite sequestration. VEGF uptake by malaria parasites was observed.
  
  
  CONCLUSIONS
  VEGF and its receptor expression levels in severe malaria reflect a non-specific response to severe systemic disease. Potential manipulation of events at the vasculature by the parasite requires further investigation.
authors: Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK. isabelle.medana@ndcls.ox.ac.uk
authors: Isabelle M
authors: IM
authors: Medana
authors: Nicholas P J
authors: NP
authors: Day
authors: Rachel
authors: R
authors: Roberts
authors: Navakanit
authors: N
authors: Sachanonta
authors: Helen
authors: H
authors: Turley
authors: Emsri
authors: E
authors: Pongponratn
authors: Tran Tinh
authors: TT
authors: Hien
authors: Nicholas J
authors: NJ
authors: White
authors: Gareth D H
authors: GD
authors: Turner
mesh_terms: D000328:Adult; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D016022:Case-Control Studies; D006801:Humans; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D055806:Microvessels / Q000469:parasitology; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2