Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2013

Open Access 01-12-2013 | Research

A clinicopathological correlation of the expression of the angiopoietin-Tie-2 receptor pathway in the brain of adults with Plasmodium falciparum malaria

Authors: Panote Prapansilp, Isabelle Medana, Nguyen Thi Hoan Mai, Nicholas PJ Day, Nguyen Hoan Phu, Tsin W Yeo, Tran Tinh Hien, Nicholas J White, Nicholas M Anstey, Gareth DH Turner

Published in: Malaria Journal | Issue 1/2013

Login to get access

Abstract

Background

Plasma angiopoietin (Ang)-2 is associated with disease severity and mortality in adults and children with falciparum malaria. However the mechanism of action of the angiopoietins in fatal malaria is unclear. This study aimed to determine whether the expression of Ang-1 and Ang-2 and their receptor Tie-2 in cerebral endothelial or parenchymal cells was specific to cerebral malaria (CM), correlated with coma or other severe clinical features, and whether plasma and CSF levels of these markers correlated with the clinical and neuropathological features of severe and fatal malaria in Vietnamese adults.

Methods

Immunohistochemistry was performed for Ang-1, Ang-2 and Tie-2 on post-mortem brain tissue from fatal malaria cases and controls. Quantitative ELISA for plasma and cerebrospinal fluid levels of Ang-1, Ang-2 and Tie-2 was done to compare fatal cases with surviving patients from the same study.

Results

Immunohistochemistry revealed significant differences in expression in endothelial and parenchymal cells compared to controls. However there was no significant difference in expression of these markers on endothelial cells, astroglial cells or neurons between CM and non-cerebral malaria cases. Immunostaining of Ang-1, Ang-2 and Tie-2 was also not associated with Plasmodium falciparum-infected erythrocyte sequestration in the brain. However Ang-1 and Ang-2 expression in neurons was significantly correlated with the incidence of microscopic haemorrhages. Plasma levels of Ang-2 and Ang-2/Ang-1 ratio were associated with the number of severe malaria complications and were significant and independent predictors of metabolic acidosis and fatal outcome.

Conclusions

The independent prognostic significance of Ang-2 and the Ang-2/Ang-1 ratio in severe malaria was confirmed, although immunohistochemistry in fatal cases did not reveal increased expression on brain endothelium in cerebral versus non-cerebral cases. Activation of the Ang-Tie-2 pathway in severe malaria is therefore related to acidosis, number of severity criteria and outcome, but is not a specific event in the brain during cerebral malaria.
Appendix
Available only for authorised users
Literature
1.
World Health Organization: World malaria report 2011. 2012, Geneva: World Health Organization
2.
World Health Organization: Severe falciparum malaria. Tran R Soc Trop Med Hyg. 2000, 94 (Suppl 1): S1-S90.CrossRef
3.
Idro R, Otieno G, White S, Kahindi A, Fegan G, Ogutu B, Mithwani S, Maitland K, Neville BGR, Newton CRJC: Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria. Malar J. 2005, 4: 57-10.1186/1475-2875-4-57.PubMedCentralCrossRefPubMed
4.
Pongponratn E, Riganti M, Punpoowong B, Aikawa M: Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. AmJTrop Med Hyg. 1991, 44: 168-175.
5.
Pongponratn E, Turner GDH, Day NPJ, Phu N, Simpson JA, Stepniewska K, Mai NTH, Viriyavejakul P, Looareesuwan S, Hien TT: An Ultrastructural study of the brain in fatal plasmodium falciparum malaria. AmJTrop Med Hyg. 2003, 69: 345-359.
6.
Silamut K, Phu NH, Whitty C, Turner GDH, Louwrier K, Mai NTH, Simpson JA, Hien TT, White NJ: A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol. 1999, 155: 395-410. 10.1016/S0002-9440(10)65136-X.PubMedCentralCrossRefPubMed
7.
Dorovini-Zis K, Schmidt K, Huynh H, Fu WJ, Whitten RO, Milner DA, Kamiza SB, Molyneux ME, Taylor TE: The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011, 178: 2146-2158. 10.1016/j.ajpath.2011.01.016.PubMedCentralCrossRefPubMed
8.
Medana IM, Turner GDH: Human cerebral malaria and the blood–brain barrier. Int J Parasitol. 2006, 36: 555-568. 10.1016/j.ijpara.2006.02.004.CrossRefPubMed
9.
Turner GDH, Morrison H, Jones M, Davis TM, Looareesuwan S, Buley ID, Gatter KC, Newbold CI, Pukritayakamee S, Nagachinta B: An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol. 1994, 145: 1057-1069.PubMedCentralPubMed
10.
Turner GDH, Ly VC, Nguyen TH, Tran TH, Nguyen HP, Bethell DB, Wyllie S, Louwrier K, Fox SB, Gatter KC, Day NP, Tran TH, White NJ, Berendt AR: Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. Am J Pathol. 1998, 152: 1477-1487.PubMedCentralPubMed
11.
Nag S, Manias J, Stewart DJ: Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol. 2009, 118: 197-217. 10.1007/s00401-009-0541-0.CrossRefPubMed
12.
Dejana E, Tournier-Lasserve E, Weinstein BM: The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell. 2009, 16: 209-221. 10.1016/j.devcel.2009.01.004.CrossRefPubMed
13.
Fiedler U, Augustin H: Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006, 27: 552-558. 10.1016/j.it.2006.10.004.CrossRefPubMed
14.
Hawkins BT, Davis TP: The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005, 57: 173-185. 10.1124/pr.57.2.4.CrossRefPubMed
15.
Pfaff D, Fiedler U, Augustin HG: Emerging roles of the angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking. J Leuk Biol. 2006, 80: 719-726. 10.1189/jlb.1105652.CrossRef
16.
Pober JS, Sessa WC: Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007, 7: 803-815. 10.1038/nri2171.CrossRefPubMed
17.
Rondaij M, Bierings R, Kragt A, van Mourik JA, Voorberg J: Dynamics and plasticity of weibel-palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol. 2006, 26: 1002-1007. 10.1161/01.ATV.0000209501.56852.6c.CrossRefPubMed
18.
Fiedler U, Scharpfenecker M, Koidl S, Hegen A, Grunow V, Schmidt JM, Kriz W, Thurston G, Hellmut G, Augustin HG: The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell weibel-palade bodies. Blood. 2004, 103: 4150-4156. 10.1182/blood-2003-10-3685.CrossRefPubMed
19.
Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006, 12: 235-239. 10.1038/nm1351.CrossRefPubMed
20.
Xu Y: Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem. 2001, 276: 34990-34998. 10.1074/jbc.M103661200.CrossRefPubMed
21.
Makinde T, Agrawal DK: Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease. J Cell Mol Med. 2008, 12: 810-828. 10.1111/j.1582-4934.2008.00254.x.PubMedCentralCrossRefPubMed
22.
Huang YQ, Li JJ, Hu L, Lee M, Karpatkin S: Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood. 2002, 99: 1646-1650. 10.1182/blood.V99.5.1646.CrossRefPubMed
23.
Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y: Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem. 1999, 274: 15732-15739. 10.1074/jbc.274.22.15732.CrossRefPubMed
24.
Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, Price RN, Duffull SB, Celermajer DS, Anstey NM: Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci USA. 2008, 105: 17097-17102. 10.1073/pnas.0805782105.PubMedCentralCrossRefPubMed
25.
Jain V, Lucchi NW, Wilson NO, Blackstock AJ, Nagpal AC, Joel PK, Singh MP, Udhayakumar V, Stiles JK, Singh N: Plasma levels of angiopoietin-1 and −2 predict cerebral malaria outcome in central India. Malar J. 2011, 10: 383-10.1186/1475-2875-10-383.PubMedCentralCrossRefPubMed
26.
Conroy AL, Lafferty EI, Lovegrove FE, Krudsood S, Tangpukdee N, Liles WC, Kain KC: Whole blood angiopoietin-1 and −2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J. 2009, 8: 295-10.1186/1475-2875-8-295.PubMedCentralCrossRefPubMed
27.
Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, Hawkes M, Krudsood S, Looareesuwan S, John CC, Liles WC, Kain KC: Serum angiopoietin-1 and −2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One. 2009, 4: e4912-10.1371/journal.pone.0004912.PubMedCentralCrossRefPubMed
28.
Conroy AL, Phiri H, Hawkes M, Glover S, Mallewa M, Seydel KB, Taylor TE, Molyneux ME, Kain KC: Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case–control study. PLoS One. 2010, 5: e15291-10.1371/journal.pone.0015291.PubMedCentralCrossRefPubMed
29.
Conroy AL, Glover SJ, Hawkes M, Erdman LK, Seydel KB, Taylor TE, Molyneux ME, Kain KC: Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case–control study. Crit Care Med. 2012, 40: 952-959. 10.1097/CCM.0b013e3182373157.PubMedCentralCrossRefPubMed
30.
Ohab JJ, Fleming S, Blesch A, Carmichael ST: A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006, 26: 13007-13016. 10.1523/JNEUROSCI.4323-06.2006.CrossRefPubMed
31.
Hien TT, Day NP, Phu NH, Mai NTH, Chau TT, White NJ: A controlled trial of Artemether or quinine in Vietnamese adults with severe falciparum malaria. NEJM. 1996, 335: 76-83. 10.1056/NEJM199607113350202.CrossRef
32.
World Health Organization: Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990, 84: 1-65.CrossRef
33.
Medana IM, Mai NT, Day NP, Hien TT, Bethell D, Phu NH, Farrar J, White NJ, Turner GD: Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal plasmodium falciparum malaria. Neuropathol Appl Neurobiol. 2001, 27: 421-433. 10.1046/j.0305-1846.2001.00360.x.CrossRefPubMed
34.
Medana IM, Day NPJ, Hien TT, Mai NTH, Bethell DB, Phu NH, Farrar J, Esiri MM, White NJ, Turner GDH: Axonal injury in cerebral malaria. Am J Pathol. 2002, 160: 655-666. 10.1016/S0002-9440(10)64885-7.PubMedCentralCrossRefPubMed
35.
Medana IM, Hien TT, Day NPJ, Phu NH, Mai NTH, Chuong LV, Chau TTH, Taylor A, Salahifar H, Stocker R, Smythe G, Turner GD, Farrar J, White NJ, Hunt NH: The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malaria. J Infect Dis. 2002, 185: 650-656. 10.1086/339009.CrossRefPubMed
36.
Ponsford MJ, Medana IM, Prapansilp P, Hien TT, Lee SJ, Dondorp AM, Esiri MM, Day NPJ, White NJ, Turner GDH: Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis. 2012, 205: 663-671. 10.1093/infdis/jir812.PubMedCentralCrossRefPubMed
37.
Day NPJ, Hien TT, Schollaardt T, Loc PP, Chuong LV, Chau TTH, Mai NTH, Phu NH, Sinh DX, White NJ, Ho M: The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J Infect Dis. 1999, 180: 1288-1297. 10.1086/315016.CrossRefPubMed
38.
Day NPJ, Phu NH, Mai NTH, Chau TTH, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ: The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med. 2000, 28: 1833-1840. 10.1097/00003246-200006000-00025.CrossRefPubMed
39.
Erdman LK, Dhabangi A, Musoke C, Conroy AL, Hawkes M, Higgins S, Rajwans N, Wolofsky KT, Streiner DL, Liles WC, Cserti-Gazdewich CM, Kain KC: Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case–control study. PLoS One. 2011, 6: e17440-10.1371/journal.pone.0017440.PubMedCentralCrossRefPubMed
40.
Li JJ, Huang YQ, Basch R, Karpatkin S: Thrombin induces the release of angiopoietin-1 from platelets. J Thromb Haemost. 2001, 85: 204-206.
41.
Maneerat Y, Viriyavejakul P, Punpoowong B, Jones M, Wilairatana P, Pongponratn E, Turner GDH, Udomsangpetch R: Inducible nitric oxide synthase expression is increased in the brain in fatal cerebral malaria. Histopath. 2000, 37: 269-277. 10.1046/j.1365-2559.2000.00989.x.CrossRef
42.
Medana IM, Day NPJ, Roberts R, Sachanonta N, Turley H, Pongponratn E, Hien TT, White NJ, Turner GDH: 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. Histopath. 2010, 57: 282-294. 10.1111/j.1365-2559.2010.03619.x.CrossRef
43.
Phiri HT, Bridges DJ, Glover SJ, van Mourik JA, de Laat B, Mbaya B, Taylor TE, Seydel KB, Molyneux ME, Faragher EB, Craig AG, Bunn JE: Elevated plasma von willebrand factor and propeptide levels in Malawian children with malaria. PLoS One. 2011, 6: e25626-10.1371/journal.pone.0025626.PubMedCentralCrossRefPubMed
44.
Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CF, Nosten F, Chapman D, Brewster D, Holloway PA, White NJ: Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg. 1994, 88: 67-73. 10.1016/0035-9203(94)90504-5.CrossRefPubMed
45.
Agbenyega T, Angus BJ, Bedu-Addo G, Baffoe-Bonnie B, Guyton T, Stacpoole PW, Krishna S: Glucose and lactate kinetics in children with severe malaria. J Clin Endocrinol Metab. 2000, 85: 1569-1576. 10.1210/jc.85.4.1569.PubMed
46.
Kosacka J, Figiel M, Engele JR, Hilbig H, Majewski M, Spanel-Borowski K: Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells positive for Tie-2 receptor. Cell Tissue Res. 2005, 320: 11-19. 10.1007/s00441-004-1068-2.CrossRefPubMed
47.
Bai Y, Cui M, Meng Z, Shen L, He Q, Zhang X, Chen F, Xiao J: Ectopic expression of angiopoietin-1 promotes neuronal differentiation in neural progenitor cells through the Akt pathway. Biochem Biophys Res Commun. 2009, 378: 296-301. 10.1016/j.bbrc.2008.11.052.CrossRefPubMed
48.
Valable S: Angiopoietin-1-induced phosphatidyl-inositol 3-kinase activation prevents neuronal apoptosis. FASEB J. 2003, 17: 443-445.PubMed
49.
Bai Y, Meng Z, Cui M, Zhang X, Chen F, Xiao J, Shen L, Zhang Y: An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. Neuroscience. 2009, 160: 371-381. 10.1016/j.neuroscience.2009.01.076.CrossRefPubMed
50.
Medana IM, Day NPJ, Sachanonta N, Mai NTH, Dondorp AM, Pongponratn E, Hien TT, White NJ, Turner GDH: Coma in fatal adult human malaria is not caused by cerebral oedema. Malar J. 2011, 10: 267-10.1186/1475-2875-10-267.PubMedCentralCrossRefPubMed
51.
Macmillan CJ, Starkey RJ, Easton AS: Angiogenesis is regulated by angiopoietins during experimental autoimmune encephalomyelitis and is indirectly related to vascular permeability. J Neuropathol Exp Neurol. 2011, 70: 1107-1123.CrossRefPubMed
52.
Chen X, Fu W, Tung CE, Ward NL: Angiopoietin-1 induces neurite outgrowth of PC12 cells in a Tie2-independent, beta1-integrin-dependent manner. Neurosci Res. 2009, 64: 348-354. 10.1016/j.neures.2009.04.007.PubMedCentralCrossRefPubMed
53.
Liu XS, Chopp M, Zhang RL, Buller B, Lu M, Zhang ZG: Angiopoietin 2 mediates the differentiation and migration of neural progenitor cells in the subventricular zone after stroke. J Biol Chem. 2009, 284: 22680-22689. 10.1074/jbc.M109.006551.PubMedCentralCrossRefPubMed
Metadata
Title
A clinicopathological correlation of the expression of the angiopoietin-Tie-2 receptor pathway in the brain of adults with Plasmodium falciparum malaria
Authors
Panote Prapansilp
Isabelle Medana
Nguyen Thi Hoan Mai
Nicholas PJ Day
Nguyen Hoan Phu
Tsin W Yeo
Tran Tinh Hien
Nicholas J White
Nicholas M Anstey
Gareth DH Turner
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2013
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-12-50

Other articles of this Issue 1/2013

Malaria Journal 1/2013 Go to the issue

Methodology

Methods for implementing a medicine outlet survey: lessons from the anti-malarial market

Research

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

Research

Serum lipids and lipoproteins in malaria - a systematic review and meta-analysis

Research

Prevalence and molecular basis of glucose-6-phosphate dehydrogenase deficiency in Afghan populations: implications for treatment policy in the region

Research

Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate

Research

Physical durability of PermaNet 2.0 long-lasting insecticidal nets over three to 32 months of use in Ethiopia
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits