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.
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.
Medana
Isabelle M
IM
Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK. isabelle.medana@ndcls.ox.ac.uk
Day
Nicholas P J
NP
Roberts
Rachel
R
Sachanonta
Navakanit
N
Turley
Helen
H
Pongponratn
Emsri
E
Hien
Tran Tinh
TT
White
Nicholas J
NJ
Turner
Gareth D H
GD
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
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