Intrathecal production and secretion of vascular endothelial growth factor during cryptococcal meningitis

Frank E.J. Coenjaerts*, Michiel Van Der Flier, Pauline N.M. Mwinzi, Annemarie E. Brouwer, Jelle Scharringa, Wendy S. Chaka, Marieke Aarts, Adul Rajanuwong, David A. Van De Vijver, Tom S. Harrison, Andy I.M. Hoepelman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)


Background. Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM. Methods. We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro. Results. Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P < .001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P = .005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P < .001), plasma (P = .028), and serum (P < .001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally. Conclusions. Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4+ T lymphocytes-stimulated by monocytes acting as antigen-presenting cells-are the cells that produce VEGF in response to cryptococcal antigens.

Original languageEnglish
Pages (from-to)1310-1317
Number of pages8
JournalJournal of Infectious Diseases
Issue number7
Publication statusPublished - 1 Oct 2004
Externally publishedYes

Bibliographical note

Funding Information:
Financial support: Medical Branch of the Dutch Sciences Organization (NWO-MW AGIKO 920-03-077 to M.v.d.F.); Utrecht Scholarship Program, UtrechtUniversity (fellowship to P.N.M.M.); Lancet International Fellowship (RH/H9-140202 to A.E.B.); Wellcome Trust Advanced Training Fellowship (GRO52199 to T.S.H.).


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