Biol. Pharm. Bull. 28(1) 1—8 (2005)

key role in vision, has a blood-retinal barrier (BRB) to maintain a constant milieu and shield the neural retina from the circulating blood. The BRB forms complex tight junctions of retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (RPE; outer BRB). The inner two thirds of the human retina is nourished by retinal capillaries and the remainder is covered by choriocapillaris via the outer BRB. In addition to the BRB, the blood-aqueous barrier, which is formed by epithelial barriers of the cilliary body and by the iridial endothelial cells, is present in the anterior segment of the eye to maintain aqueous humor conditions. Both barriers form the so-called blood-ocular barrier (Fig. 1). The concept of the BRB was first proposed by Schnaudigel in 1913 following the classical work of Ehrlich and Goldman who discovered the blood-brain barrier (BBB). The inner BRB is structurally similar to the BBB and the retinal capillary endothelial cells are covered with pericytes and glial cells. Glial Müller cells predominantly support retinal endothelial cells, although glial astrocytes play a major role in supporting endothelial functions at the BBB and also, partly, at the inner BRB (Fig. 1). Many groups have carried out detailed investigations of the transport functions at the BBB and Cornford postulated that the BBB acts as a dynamic regulatory interface. Since then, many influx and efflux transporters have been identified and characterized at the BBB. It was believed that the transport functions at the inner BRB are the same as those at the BBB. Nevertheless, information about transport functions and transporters at the inner BRB is very limited. Until 1999, only three transporters, i.e. facilitative D-glucose transporter (GLUT)1, monocarboxylate transporter (MCT)1, and Pglycoprotein (P-gp), had been identified immunohistochemically at the inner BRB. This lack of interest in this aspect of vision research is somewhat surprising, given that the inner BRB plays important roles in supplying nutrients to the neural retina and is responsible for the efflux of neurotransmitter metabolites from the retina to maintain neural functions. In vivo transport studies using the Retinal Uptake Index (RUI) method have been performed to investigate solute transport into the retina. Although these have the advantage of being able to estimate the ability to transport solutes from the circulating blood to the retina under physiological conditions, it is difficult to distinguish between substrates that are taken up by the inner BRB and the outer BRB. In order to successfully identify the transporters and transport mechanisms at the inner BRB, we need to develop a good in vitro system, which accurately reflects in vivo transport functions. The techniques of isolation and primary culture of bovine retinal capillaries have been applied to studies of the inner BRB. However, it is not easy to carry out a series of transport experiments since only 170—250 mg protein (capillary) can be obtained from a single bovine eye and, recently, bovine spongiform encephalopathy has presented a serious social problem. Thus, it is important to develop retinal capillary endothelial cell lines which reflect in vivo transport functions and remain reproducible during multiple passages in order to elucidate transport mechanisms and identify transporters at the inner BRB. The results of such studies should provide useful information for the treatment of retinal vascular disease and macular pathology, as well as allowing more specific retinal drug targeting. The loss of pericytes in retinal capillaries is one of the earliest changes in diabetic retinopathy and this causes angiogenesis due to an increase in retinal endothelial cells. Therefore, the growth of endothelial cells is thought to be regulated by pericytes and studies of cell-to-cell interactions between retinal endothelial cells and pericytes are important to elucidate the mechanisms responsible for the onset of diabetic retinopathy. In this review, we shall focus on the cell characteristics, transport functions, and cell-to-cell interactions of newly developed rat retinal capillary endothelial cells, pericytes, and January 2005 Biol. Pharm. Bull. 28(1) 1—8 (2005) 1