Macromolecular depletion modulates the binding of red blood cells to activated endothelial cells

Abstract

Adhesion of red blood cells (RBCs) to endothelial cells (ECs) is usually insignificant but an enhanced adhesion has been observed in various diseases associated with vascular complications. This abnormal adhesion under pathological conditions such as sickle cell disease has been correlated with increased levels of various plasma proteins but the detailed underlying mechanism(s) remains unclear. Usually it is assumed that the proadhesive effects of plasma proteins originate from ligand interactions cross-linking receptors on adjacent cells, but explicit results detailing binding sites or receptors for some proteins (e.g., fibrinogen) on either RBC or EC surfaces that would support this model are missing. In this study, the authors tested whether there is an alternative mechanism. Their results demonstrate that dextran 2 MDa promotes the adhesion of normal RBCs to thrombin-activated ECs and that this effect becomes more pronounced with increasing thrombin concentration or with prolonged thrombin incubation time. It is concluded that depletion interaction originating from nonadsorbing macromolecules (i.e., dextran) can modulate the adhesion of red blood cells to thrombin-activated EC. This study thereby suggests macromolecular depletion as an alternative mechanism for the adhesion-promoting effects of nonadsorbing plasma proteins. These findings should not only aid in getting a better understanding of diseases associated with vascular complications but should also have many potential applications in biomedical or biotechnological areas that require the control of cell-cell or cell surface interactions.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part I: Astrocyte

“…Additionally, the inner plasma membrane may translocate phosphatidylserine (PS) to the outer leaflet in the hyperglycemic microenvironment of DBC models. The translocated or "flipped" outer leaflet PS will contribute to the adherence of RBCs to the EC PS receptor, as well as to the EC matrix of thrombospondin, αvβ1, and CD36, which may add to the increased electron density of the proteinaceous electron-dense adhesion plaques of the RBC and EC [41,42]. Importantly, there were also adherent mononuclear white blood cells within the capillary lumen of NVUs observed in the cortical gray matter in DBC models, as depicted in previous figures ( Figures 4C,D, 7C and 8B), which will be discussed in greater detail as they relate to microglia remodeling.…”

Macromolecular depletion as a determinant of RBC adhesive interactions: Why blood is thicker than water

“…In fact, industrial applications of depletion flocculation are wide spread, including removing small particles from industrial waste by aggregating these particles, thus allowing mechanical separation from the fluid phase. However, this mechanism has only received minimal recognition in biological systems, even though the existence of depletion layers and the applicability of the depletion model to adhesive interactions of blood cells have been demonstrated in several recent studies [4,5,7,24,25,34,[43][44][45]47].…”

“…However, several findings that are more recent have shown that depletion interaction plays a major role in RBC-RBC interactions by providing the attractive force causing RBC come into close proximity and form aggregates [4,6,24,25]. Depletion-mediated forces are also a major determinant of RBC-EC adhesion in that they bring cells into close contact, thereby allowing or inducing the formation of stronger specific bonds [25,27,41,[43][44][45].…”

“…In a series of publications, the clear answer has been shown to be "yes". For example, the adhesion of normal RBC is markedly increased in the presence of dextran with a molecular mass greater than 70 kDa [41,45] and specific binding of RBC is significantly enhanced in the presence of non-absorbing macromolecules such as dextran [42][43][44][45]. Interestingly, while 70 kDa dextran promotes RBC aggregation [40] and RBC adhesion to albumin-coated glass [41], it does not induce RBC adhesion to cultured endothelial cells [27], most likely due to differing surface characteristics (e.g., thickness, permeability) between protein adsorbed on glass and endothelial cells grown on a flat surface.…”