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Published on: July 24, 2016
Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis
Frank E J Coenjaerts1, Michiel van der Flier, Pauline N M Mwinzi
1Department of Acute Medicine and Infectious Diseases and Eijkman-Winkler Institute for Microbiology, University Medical Center Utrecht, The Netherlands. f.e.j.coenjaerts@lab.azu.nl.
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.
Insights
Vascular Endothelial Growth Factor (VEGF) is elevated in patients with cryptococcal meningitis (CM), suggesting it plays a key role in the disease. This study identifies immune cells producing VEGF in response to cryptococcal antigens.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Cryptococcal meningitis (CM) frequently causes elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption.
- Elevated ICP is a major factor contributing to mortality in CM patients.
- Vascular Endothelial Growth Factor (VEGF) is implicated as a potential mediator of BBB disruption in CM.
Purpose of the Study:
- To investigate the role of VEGF in the pathophysiology of CM.
- To measure VEGF levels in patients with CM and healthy controls.
- To identify the cellular sources and triggers of VEGF secretion in vitro.
Main Methods:
- Measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) from 95 CM patients and 63 controls.
- Analyzed in vitro VEGF secretion induced by Cryptococcus neoformans antigens.
- Utilized major histocompatibility complex class II antibody to investigate VEGF production pathways.
Main Results:
- Cryptococcal antigens dose-dependently induced VEGF secretion from neutrophils, monocytes, and PBMCs.
- VEGF production by PBMCs was significantly higher than by monocytes.
- Patients with CM exhibited significantly elevated VEGF levels in CSF, plasma, and serum compared to controls, indicating intrathecal production.
Conclusions:
- VEGF is implicated in the pathophysiology of cryptococcal meningitis.
- VEGF is produced intrathecally in response to cryptococcal antigens.
- CD4(+) T lymphocytes, stimulated by monocytes, are proposed as the primary producers of VEGF in CM.
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