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The endothelium is recognized to play an important role in various physiological functions including vascular tone, permeability, anticoagulation, and angiogenesis. Endothelial dysfunction is increasingly recognized to contribute to pathophysiology of many disease states, and depending on the disease stimuli, mechanisms underlying the endothelial dysfunction may be markedly different. As such, numerous techniques to measure different aspects of endothelial dysfunction have been developed and refined as available technology improves. Current available reviews on quantifying endothelial dysfunction generally concentrate on a single aspect of endothelial function, although diseases may affect more than one aspect of endothelial function. Here, we aim to provide an overview on the techniques available for the assessment of the different aspects of endothelial function in humans, human tissues or cells, namely vascular tone modulation, permeability, anticoagulation and fibrinolysis, and the use of endothelial biomarkers as predictors of outcomes.

The impact of falling parasite prevalence on anti-Plasmodium falciparum serological indicators in pregnant women varies by setting. Increased ITN coverage may affect development of antibodies to recombinant antigens, but levels of opsonizing IgG remained stable over time. Opsonizing IgG against placental-binding IEs may persist, thus offering longer-lasting protection against malaria during pregnancy.

Pregnant women in malaria-endemic regions are susceptible to malaria in pregnancy, which has adverse consequences on birth outcomes, including having small for gestational age and preterm babies. These babies are likely to have low birthweights, which predisposes to infant mortality and lifelong morbidities. During malaria in pregnancy, Plasmodium falciparum-infected erythrocytes express a unique variant surface antigen, VAR2CSA, that mediates sequestration in the placenta. This process may initiate a range of host responses that contribute to placental inflammation and dysregulated placental development, which affects placental vasculogenesis, angiogenesis and nutrient transport. Collectively, these result in the impairment of placental functions, affecting fetal development. In this review, we provide an overview of malaria in pregnancy and the different pathological pathways leading to malaria in pregnancy-associated low birthweight. We also discuss current prevention and management strategies for malaria in pregnancy, and some potential therapeutic interventions that may improve birth outcomes. Lastly, we outline some priorities for future research that could bring us one step closer to reducing this health burden.

Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) and SP plus azithromycin (SPAZ) reduces low birthweight (<2,500 g) in women without malarial and reproductive tract infections. This study investigates the impact of SPAZ on associations between plasma biomarkers of inflammation and angiogenesis and adverse pregnancy outcomes in 2,012 Papua New Guinean women. Concentrations of C-reactive protein (CRP), α-1-acid glycoprotein (AGP), soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured at enrolment and delivery in a trial comparing SPAZ to SP plus chloroquine (SPCQ). At antenatal enrolment higher CRP (adjusted odds ratio 1.52; 95% confidence interval [CI] 1.03–2.25), sEng (4.35; 1.77, 10.7) and sFlt1 (2.21; 1.09, 4.48) were associated with preterm birth, and higher sEng with low birthweight (1.39; 1.11,3.37), in SPCQ recipients only. Increased enrolment sFlt1:PlGF ratios associated with LBW in all women (1.46; 1.11, 1.90). At delivery, higher AGP levels were strongly associated with low birthweight, preterm birth and small-for-gestational age babies in the SPCQ arm only. Restricting analyses to women without malaria infection did not materially alter these relationships. Women receiving SPAZ had lower delivery AGP and CRP levels (p < 0.001). SPAZ may protect against adverse pregnancy outcomes by reducing inflammation and preventing its deleterious consequences, including dysregulation of placental angiogenesis, in women with and without malarial infection.

Malaria remains a global health burden with Plasmodium falciparum accounting for the highest mortality and morbidity. Malaria in pregnancy can lead to the development of placental malaria, where P. falciparum-infected erythrocytes adhere to placental receptors, triggering placental inflammation and subsequent damage, causing harm to both mother and her infant. Histopathological studies of P. falciparum-infected placentas revealed various placental abnormalities such as excessive perivillous fibrinoid deposits, breakdown of syncytiotrophoblast integrity, trophoblast basal lamina thickening, increased syncytial knotting, and accumulation of mononuclear immune cells within intervillous spaces. These events in turn, are likely to impair placental development and function, ultimately causing placental insufficiency, intrauterine growth restriction, preterm delivery and low birth weight. Hence, a better understanding of the mechanisms behind placental alterations and damage during placental malaria is needed for the design of effective interventions. In this review, using evidence from human studies and murine models, an integrated view on the potential mechanisms underlying placental pathologies in malaria in pregnancy is provided. The molecular, immunological and metabolic changes in infected placentas that reflect their responses to the parasitic infection and injury are discussed. Finally, potential models that can be used by researchers to improve our understanding on the pathogenesis of malaria in pregnancy and placental pathologies are presented.

Infection with Plasmodium falciparum parasites causes the majority of malaria-related morbidity and mortality. Constant exposure to the pathogen leads to the acquisition of antibodies and high levels of antibodies have been associated with clinical protection against malaria. A possible protective mechanism is the opsonization of parasites, or malaria-infected erythrocytes (IEs), for phagocytic clearance. Current assays use adherent or chemically differentiated THP-1 cells to evaluate opsonic antibodies in patients' samples, but these assays are often time consuming and damage the effector cells. We have developed a high throughput flow cytometry-based phagocytosis assay using undifferentiated THP-1 cells to quantify the opsonic activity against late stage P. falciparum-IEs. Opsonic antibodies bound to IEs promote their phagocytic uptake through Fcγ receptors found on THP-1 cells. Moreover, undifferentiated THP-1 cells do not express CD36, a surface scavenger receptor that promotes non-opsonic phagocytosis. This technical advance allows quantification of opsonic antibodies and is an important tool for the performance of large, population-based studies of malaria immunity, and to provide a significant increase in the statistical power for such studies.

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