Endothelial Dysfunction and Microvascular Injury in Life-Threatening Diseases

Endothelial activation and dysfunction contributes to multiple life-threatening disorders including malaria, sepsis, acute lung injury (ALI) and viral haemorrhagic fevers. It represents a common pathway of injury leading to microvascular leak, multi-organ failure, mortality and long-term deficits in survivors. The detection of circulating biomarkers of the activated endothelium may enable the early detection and triage those at risk of severe disease, improving clinical outcome and prognosis. Here we investigated three life-threatening diseases (high altitude pulmonary oedema (HAPE), cerebral malaria and malaria-induced ALI) with a focus on the Ang/Tie2 pathway and its role in endothelial activation and microvascular leak. In each example, we defined the relationship of the Ang/Tie2 axis to disease pathobiology and where possible, explored mechanism and interventions based on genetic and pharmacological strategies. In a prospective case-control study of climbers developing altitude illness, we investigated mediators of endothelial activation, vascular tone and cell stress. Specifically, we show that the endothelial activation markers (endothelin-1 and soluble kinase insert domain receptor) are correlated with HAPE. We next investigated these pathways in malaria-induced cerebral microvascular injury, using in vivo and ex vivo approaches. Specifically, we show that genetic deletion of microRNA-155 enhances endothelial quiescence, blood-brain barrier integrity and survival. We suggest that these observations are likely associated with Ang/Tie2 axis dysfunction. Moreover, anti-miR-155 preserved endothelial integrity and reduced microvascular leak, induced by patient sera. Finally, we investigated these pathways in malaria-induced ALI, using sera from children with malaria-induced respiratory distress, and pre-clinical animal models. Specifically, we show that an association with Ang/Tie2 axis dysregulation and pharmacological activation of the Ang/Tie2 axis in vivo improves survival and decreases pulmonary vascular leak. In summary, these studies suggest common mediators of endothelial activation and dysfunction that play a critical role in maintaining vascular integrity, reducing microvascular leak and improving outcome from multiple different insults.Ph.D.2019-12-19 00:00:0