Mechanisms for sickle red blood cell retention in choroid

“…While we cannot unequivocally exclude the participation of leukocyte adhesion in the flow stoppage we observed, within the limits of the methodology used our results are consistent with direct adhesion of sickle RBCs to PAR-1 agonist peptide-activated endothelium having initiated vasoocclusion, as was found in rat retinal, choroidal, and cerebral microvessels in vivo. [24][25][26] …”

Section: Microvascular Flow Effects Associated With the Blocking Leukmentioning

confidence: 99%

“…Intravital microscopy has been used to document abnormal microvascular blood flow in patients with sickle cell disease 17,18 and to identify the postcapillary venules as the most common sites of sickle RBC adhesion and stoppage of blood flow in sickle cell mouse models. 19,20 Other methods of assessing blood flow in vivo also have been used, [21][22][23][24][25][26] and different mechanisms of sickle cell blood flow stoppage have been identified. These include direct adhesion of sickle RBCs to the endothelium 24-26 and leukocytemediated sickle RBC adhesions.…”

Section: Introductionmentioning

confidence: 99%

“…The evidence we provide supports a hemodynamic role of endothelial cell P-selectin on the abnormal microcirculatory flow of sickle RBCs. Much as leukocyte adhesion to the vascular endothelium is initiated by and dependent upon P-selectinmediated processes, 12 our data suggest that endothelial P-selectin is important to the endothelial adhesion of sickle RBCs.The in vivo findings by Lutty and Hillery's groups of direct adhesion of sickle RBCs to the vascular wall [24][25][26] and by Turhan and Wood and their associates of leukocyte-mediated sickle RBC adhesion 10,27 indicate that multiple adhesive mechanisms may contribute to sickle cell vasoocclusion. Our observations appear to resemble those found by Lutty and Hillery's groups.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo

Embury

Matsui²,

Ramanujam³

et al. 2004

Blood

126

121

View full text Add to dashboard Cite

Microvascular occlusion in sickle cell disease can be initiated by adhesion of sickle red blood cells (RBCs) to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBCs adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocity (V RBC ) in mice. We found faster V RBC of sickle RBCs in P-selectin knock-out and control mice than in sickle cell mice, which have increased endothelial cell P-selectin expression. Agonist peptide for murine protease-activated receptor-1 (PAR-1), which selectively activates mouse endothelial cells but not platelets, was used to assess the effects of endothelial cell Pselectin on microvascular flow. Suffusion of venules with this agonist stopped flow promptly in normal and sickle mice but not in P-selectin knock-out mice or in control mice pretreated with anti-P-selectin monoclonal antibody or unfractionated heparin (UFH). Agonist-induced slowing of flow was reversed rapidly by suffusion with UFH, provided flow had not already stopped. We conclude that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease and that blocking Pselectin may be useful for preventing painful vasoocclusion in sickle cell disease. ( IntroductionMost of the morbid consequences of sickle cell disease are caused by the impairment of blood flow in the microvasculature. 1 Traditional understandings attribute the microvascular occlusion to an increase in blood viscosity caused by intraerythrocytic polymerization of deoxygenated sickle hemoglobin and the consequent sickling and rigidification of red blood cells (RBCs). 2 Kinetic considerations predict that, in the absence of preexisting intraerythrocytic polymer, impairment of blood viscosity will occur after the RBC has entered into veins too large to be occluded by rigid sickled RBCs 3 and that polymerization will occur within vessels small enough to be occluded by individual sickled RBCs only when their transit through the microcirculation is delayed.Among the factors that can prolong the transit time of sickle RBCs through the microvasculature are several polymerizationindependent processes, including vascular constriction, coagulation, inflammation, and cellular adhesion. 4 Experimental evidence supports a 2-step mechanism of vasoocclusion initiated by the binding of an adhesive subset of sickle RBCs to the vascular endothelium and completed by the logjamming of more rigid sickle RBCs behind the adherent nidus. 5 This discovery has provided an understanding of the onset of painful vasoocclusion that is lacking from detailed explications of hemoglobin S polymerization and RBC sickling and notions of systemic deoxygenation 6 and inspired a profusion of research into mechanisms of adhesion and adhesion-blocking therapies. 7,8 The expression of cytoadhesion molecules on endothelial cells isolated from the circulating blood of patients with sickle cell disease 9 and on intact endothelial c...

show abstract

“…For instance, sickle RBCs and premature erythrocytes (reticulocytes) express integrin ␣ 4 ␤ 1 (51,52), which may play a role in vaso-occlusive events (53,54) by binding VCAM-1 on endothelial cells (51,55). Enhanced levels of circulating VCAM-1 have been reported in this disease, with peak concentrations correlating with vaso-occlusive crisis (19).…”

Section: Discussionmentioning

confidence: 99%

Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin α4β1

Woodside¹,

Kram²,

Mitchell

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Cell adhesion mediated by the interaction between integrin α4β1 and VCAM-1 is important in normal physiologic processes and in inflammatory and autoimmune disease. Numerous studies have mapped the α4β1 binding sites in VCAM-1 that mediate cell adhesion; however, little is known about the regions in VCAM-1 important for regulating soluble binding. In the present study, we demonstrate that 6D VCAM-1 (an alternatively spliced isoform of VCAM-1 lacking Ig-like domain 4) binds α4β1 with a higher relative affinity than does the full-length form of VCAM-1 containing 7 Ig-like extracellular domains (7D VCAM-1). In indirect binding assays, the EC50 of soluble 6D VCAM-1 binding to α4β1 on Jurkat cells (in 1 mM MnCl2) was 2 × 10−9 M, compared with 7D VCAM-1 at 11 × 10−9 M. When used in solution to inhibit α4β1 mediated cell adhesion, the IC50 of 6D VCAM-1 was 13 × 10−9 M, compared with 7D VCAM-1 measured at 150 × 10−9 M. Removal of Ig-like domains 4, 5, or 6, or simply substituting Asp328 in domain 4 of 7D VCAM-1 with alanine, caused increased binding of soluble 7D VCAM-1 to α4β1. In contrast, cells adhered more avidly to 7D VCAM-1 under shear force, as it induced cell spreading at lower concentrations than did 6D VCAM-1. Finally, soluble 6D VCAM-1 acts as an agonist through α4β1 by augmenting cell migration and inducing cell aggregation. These results indicate that the domain 4 of VCAM-1 plays a contrasting role when VCAM-1 is presented in solution or as a cell surface-expressed adhesive substrate.

show abstract

Mechanisms for sickle red blood cell retention in choroid

Cited by 26 publications

References 35 publications

Adhesion molecules and hydroxyurea in the pathophysiology of sickle cell disease

Adhesion molecules and hydroxyurea in the pathophysiology of sickle cell disease

The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo

Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin α4β1

Contact Info

Product

Resources

About