Abstract
IntroductionThe angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to platelet number, in vivo platelet activation and inadvertent platelet activation during blood processing. We studied plasma Ang-1, Ang-2 and VEGF levels in malaria patients, taking the necessary precautions to avoid ex vivo platelet activation, and related plasma levels to platelet count and the soluble platelet activation markers P-selectin and CXCL7.MethodsPlasma levels of Ang-1, Ang-2, VEGF, P-selectin and CXCL7 were measured in CTAD plasma, minimizing ex vivo platelet activation, in 27 patients with febrile Plasmodium falciparum malaria at presentation and day 2 and 5 of treatment and in 25 healthy controls.ResultsLevels of Ang-1, Ang-2 and VEGF were higher at day 0 in malaria patients compared to healthy controls. Ang-2 levels, which is a marker of endothelial activation, decreased after start of antimalarial treatment. In contrast, Ang-1 and VEGF plasma levels increased and this corresponded with the increase in platelet number. Soluble P-selectin and CXCL7 levels followed the same trend as Ang-1 and VEGF levels. Plasma levels of these four proteins correlated strongly in malaria patients, but only moderately in controls.ConclusionIn contrast to previous studies, we found elevated plasma levels of Ang-1 and VEGF in patients with malaria resulting from in vivo platelet activation. Ang-1 release from platelets may be important to dampen the disturbing effects of Ang-2 on the endothelium. Evaluation of plasma levels of these angiogenic proteins requires close adherence to a stringent protocol to minimize ex vivo platelet activation.
Highlights
The angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity
The endothelium plays a central role in the pathophysiology of P. falciparum malaria
Circulating levels of these proteins have been determined in several studies and, collectively, these studies found reduced Ang-1 levels and elevated Ang-2 levels in patients with malaria compared to healthy controls, while data on VEGF varied across studies [8,9,10]
Summary
The angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Cytoadherence and microvascular hypoxia as central features of malaria, it may not come as a surprise that these angiogenic proteins have been studied extensively in malaria. Circulating levels of these proteins have been determined in several studies and, collectively, these studies found reduced Ang-1 levels and elevated Ang-2 levels in patients with malaria compared to healthy controls, while data on VEGF varied across studies [8,9,10]. Additional studies suggested Ang-1 and Ang-2 to be promising biomarkers to differentiate cerebral from non-cerebral malaria [11,12]
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