Protective or pathogenic effects of vascular endothelial growth factor (VEGF) as potential biomarker in cerebral malaria

Abstract

Cerebral malaria (CM) is the major lethal complication of Plasmodium falciparum infection. It is characterized by persistent coma along with symmetrical motor signs. Several clinical, histopathological, and laboratory studies have suggested that cytoadherence of parasitized erythrocytes, neural injury by malarial toxin, and excessive inflammatory cytokine production are possible pathogenic mechanisms. Although the detailed pathophysiology of CM remains unsolved, it is thought that the binding of parasitized erythrocytes to the cerebral endothelia of microvessels, leading to their occlusion and the consequent angiogenic dysregulation play a key role in the disease pathogenesis. Recent evidences showed that vascular endothelial growth factor (VEGF) and its receptor-related molecules are over-expressed in the brain tissues of CM patients, as well as increased levels of VEGF are detectable in biologic samples from malaria patients. Whether the modulation of VEGF is causative agent of CM mortality or a specific phenotype of patients with susceptibility to fatal CM needs further evaluation. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review and discuss here what it is currently known in regard to the role of VEGF in CM as well as VEGF as a potential biomarker.

Keywords: Angiogenesis,; Biomarker,; Blood–brain barrier; Cerebral malaria,; Cytokines,; Infected-red blood cells,; Vascular endothelial growth factor,.

Figure 1

Uncontrolled inflammation and infiltration of lymphocytes in brain microvessels as well as vascular dysfunction with subsequent blood–brain barrier (BBB) damage are the major features of CM. Rapture of infected red blood cells (iRBCs) releases factors that activate brain microvascular endothelial cells (ECs), leading to up-regulation of receptors for iRBC. Sequestration of iRBCs provokes local loss of endothelial protein C receptor (EPCR) and thrombomodulin, which is associated with local inflammation and disturbance of coagulation. Moreover, strong systemic inflammation further amplifies endothelial cell activation in the brain and activates brain-resident perivascular macrophages, microglia, and astrocytes. Activated endothelial and glial cells provide chemotactic signals for lymphocytes and myeloid cells. Sequestered iRBCs and leukocytes interfere with cerebral blood flow and together with cytotoxic factors, damage BBB, leading to edema and hemorrhage. The role of VEGF in this scenario is still unknown. However, at high levels of vessels sequestration there may be increased soluble VEGF production by ECs and perivascular cells as a result of local hypoxia. Vascular endothelial growth factor’s (VEGF) involvement in cerebral malaria (CM) pathogenesis.

Figure 2

In neurons the best characterized signaling pathways are VEGFR-2, PI3K/Akt, and MEK/ERK. Like VEGF A, VEGF B also seems to exert a neuro-protective effect in cerebral ischemia. Accordingly, VEGF B protects cultured cerebral cortical neurons from hypoxia, whereas infarct volume is increased and neurological function is more impaired in VEGF B-knockout that in wild-type mice. Direct neuronal impact of vascular endothelial growth factor (VEGF) and its mechanisms.

Figure 3

Vascular endothelial growth factor can induce both beneficial and detrimental effects in the pathogenesis of CM. However, its role is still controversial. The balance between protective and pathogenic roles of vascular endothelial growth factor (VEGF) in cerebral malaria (CM).