Abstract
Vaso-occlusive crises are the main acute complication in sickle cell disease. They are initiated by abnormal adhesion of circulating blood cells to vascular endothelium of the microcirculation. Several interactions involving an intricate network of adhesion molecules have been described between sickle red blood cells and the endothelial vascular wall. We have shown previously that young sickle reticulocytes adhere to resting endothelial cells through the interaction of α4β1 integrin with endothelial Lutheran/basal cell adhesion molecule (Lu/BCAM). In the present work, we investigated the functional impact of endothelial exposure to hydroxycarbamide (HC) on this interaction using transformed human bone marrow endothelial cells and primary human pulmonary microvascular endothelial cells. Adhesion of sickle reticulocytes to HC-treated endothelial cells was decreased despite the HC-derived increase of Lu/BCAM expression. This was associated with decreased phosphorylation of Lu/BCAM and up-regulation of the cAMP-specific phosphodiesterase 4A expression. Our study reveals a novel mechanism for HC in endothelial cells where it could modulate the function of membrane proteins through the regulation of phosphodiesterase expression and cAMP-dependent signaling pathways.
Highlights
Hydroxycarbamide treatment may inhibit the proadhesive features of vascular endothelium in sickle cell disease
Endothelial Lutheran/basal cell adhesion molecule (Lu/BCAM) Sustains SS Reticulocyte Adhesion to TrHBMECs—First, we addressed the endothelial characteristics of the TrHBMEC cell line by analyzing the expression of vascular cell adhesion molecule-1 (VCAM-1) at the cell surface
In the absence of VCAM-1 on resting TrHBMECs, we investigated the role of another ligand, Lu/BCAM, in sustaining this adhesion
Summary
Hydroxycarbamide treatment may inhibit the proadhesive features of vascular endothelium in sickle cell disease. Vaso-occlusive crises are the main acute complication in sickle cell disease They are initiated by abnormal adhesion of circulating blood cells to vascular endothelium of the microcirculation. Adhesion of sickle reticulocytes to HC-treated endothelial cells was decreased despite the HC-derived increase of Lu/BCAM expression This was associated with decreased phosphorylation of Lu/BCAM and up-regulation of the cAMP-specific phosphodiesterase 4A expression. The SCD classical physiological scheme involves hemoglobin S polymerization and less deformable sickle red blood cell (SS RBC) formation under hypoxic conditions In addition to their propensity to sickle, SS RBCs can abnormally adhere to the vascular endothelium, contributing to microvascular occlusions [1, 2] and to the initiation and progression of VOC which represent the main SCD acute complication [3]. We found a decreased SS reticulocyte adhesion to HC-treated endothelial cells and revealed a new mechanism where HC upregulates the expression of the cAMP-specific phosphodiesterase 4A leading to decreased levels of cAMP and Lu/BCAM phosphorylation
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