Differential Expression of E‐ and P‐Selectin in the Microvasculature of Sickle Cell Transgenic Mice

Abstract

Sickle cell disease promotes an increased P-selectin expression in several vascular beds. An accumulation of platelets may explain the increased P-selectin expression observed in some vascular beds.

Redox-dependent impairment of vascular function in sickle cell disease

“…The dual radiolabeled mAb technique enabled the quantification of E-and Pselectin expression in different vascular beds in Paszty β S transgenic mice, which are heterozygous for murine β globin and human β S . Up regulation of P-selectin was demonstrated in the lung, heart, small bowel, large bowel and penis, while E-selectin expression only increased in the penis (69).…”

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

“…4 Adhesion molecules that mediate sickle RBC adherence to the endothelium include many of the same molecules that direct leukocyte adhesion in inflammation, 7 a process that is initiated by interactions of selectins with their ligands. 12 The increased levels of endothelial cell P-selectin expression in sickle cell disease [9][10][11] and the increased production and activity of the endothelial cell agonist thrombin 13,14 suggested to us that P-selectin might have a role in sickle RBC adhesion. Work from our laboratory has demonstrated that sickle RBCs adhere to P-selectin expressed on thrombinstimulated endothelial cells and to immobilized recombinant P-selectin under both static and flow conditions in vitro, 15,16 but the importance of P-selectin-mediated sickle RBC adhesion to the microvascular blood flow in sickle cell disease has yet to be established.…”

“…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 cells in murine models of sickle cell disease 10,11 reflects the effects of the several endothelial cell agonists operational in sickle cell disease. 4 Adhesion molecules that mediate sickle RBC adherence to the endothelium include many of the same molecules that direct leukocyte adhesion in inflammation, 7 a process that is initiated by interactions of selectins with their ligands.…”

“…Rather, some microvascular properties of sickle cell mice accounted for the slower V RBC observed. The increased adhesivity of sickle RBCs for P-selectin, 15 the similar rapid mean V RBC observed in P-selectin knock-out and C57BL/6 mice in which endothelial cell P-selectin expression had not been activated, and the slower V RBC in sickle cell mice, which have chronically greater levels of endothelial P-selectin expression, 10,11 suggest that the level of P-selectin expression may be the vascular property of sickle cell mice responsible for the slower V RBC observed.To explore further the determinants of microvascular hemodynamics we compared the flow rates of sickle and normal mouse RBCs in medium-size venules of C57BL/6 mice. The V RBC of XRITC-labeled normal (n ϭ 18) and sickle (n ϭ 24) RBCs in medium-size venules (20 to 40 m diameter) were not statistically different (V RBC ϭ 2.71 Ϯ 0.18 mm/s and 3.06 Ϯ 0.13 mm/s, respectively; P ϭ .1).…”

Pachymeningeal involvement in POEMS syndrome: Dramatic cerebral MRI improvement after lenalidomide therapy

“…In the interest of determining an accurate predictive pharmacogenetic algorithm to promote rational treatment, especially for Chinese outliers, we attempted to assess the predictive ability of published warfarin pharmacogenetic dosing algorithms in Mainland Han Chinese [12][13][14][15][16][17][18][19].…”