Probing the mechanistic basis of two distinct endothelial barrier phenotypes in health and disease

Introduction: Vascular endothelial cells form the primary barrier to free blood-tissue exchange. Large vessels and capillaries in CNS are covered by continuous endothelium. The continuous phenotype has low number of vesicles and connected by tight junctions, which forms blood-brain barrier (BBB) and blood-retina barrier (BRB). Breakdown of BBB/BRB results to vascular dysfunction, leakage and tissue edema. In the contrast, fenestrated endothelium allows rapid blood-tissue exchange and is present at sites of filtration, secretion and absorption. Abnormality of endothelium fenestration results to change in vascular permeability, nutrients deprivation of tissue and debris accumulation, which further leads to cascades of pathological progressing. Aim: To understand the mechanistic basis of the two distinct endothelial barrier phenotypes, to identify factors regulating blood-retinal barrier breakdown and endothelium fenestration, and to manipulate them therapeutically for vascular diseases. Conclusion 1: Blood-retinal barrier breakdown in ocular diseases resulted to vascular leakage and tissue oedema. Identification of underlying mechanism is essential to develop novel therapeutics for vascular diseases. Conclusion 2: Our in vitro cell model provided a great tool to identify components of fenestra, the in vivo transportation assay enables us to explore the direct role of choriocapillary fenestrae in substance transportation through choriocapillary-Bruch’s membrane-RPE complex. The findings will aid the development of novel therapeutic target for age-related vascular diseases, particularly, AMD