Fig. 5.

Leukocyte and vascular changes in chronic hyperglycemia. In physiological conditions, circulating leukocytes are constantly passing through narrow capillaries with smaller diameters than their own, resulting in direct contact with endothelial cells. This results in temporary rolling along the inner vessel wall via P-selectin–PSGL-1 interactions. In the postcapillary segment, they detach and continue circulating (left side, under ‘normal’). High blood glucose levels and the resulting advanced glycation end-products (AGEs) lead to both priming of leukocytes and endothelial cell changes which favor longer interaction between the two. We showed here that P-selectin on endothelial cells and its ligand PSGL-1 on leukocytes are overexpressed, which may in part explain the observed high rolling rate in vivo. Prolonged leukocyte–endothelial cell interaction may also promote release of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNs) directly against the vessel wall by favoring both proximity and cell activation. Furthermore, changes in endothelial cell phenotype and the basement membrane structure may explain the increased permeability for large molecules (right side, under ‘diabetes’).