Clonal senescence alters endothelial ICAM-1 function

Little is known how age alters the dynamics and function of cell adhesion molecules, especially under inflammatory and stressful conditions. One membrane constituent, intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein of the immunoglobulin (Ig) superfamily that regulates key outside -> in and inside -> out signals associated with cell-to-cell interactions. If conditions such as age and inflammation change usual ICAM-1 action then important downstream effects ultimately perturb endothelial cell function. In this report, ICAM-1 accumulates in late passage endothelial cells when compared to early passage endothelial cells, yet ICAM-1 protein expression is attenuated when senescent cells are challenged by TNF-alpha (10 ng/ml). Importantly, age alters ICAM-1 dynamic properties from directed to random receptor motion within the membrane. Single particle tracking reveals that the average ICAM-1 mobility is 44% less in late than early passage cells after its motion is stimulated by the Protein Kinase C (PKC) activator, phorbol myristate acetate (PMA). The mechanism for altered ICAM-1 mobility partly can be explained by a reduced rate of alpha-actinin linking with ICAM-1 in late passage Human Pulmonary Artery Endothelial Cells (HPAECs). Furthermore, tyrosine phosphorylation of alpha-actinin, a requirment for ICAM-1 clustering, is markedly reduced in senescent cells. These findings support a hypothesis that senescence results in changes of 1CAM-1 activation and clustering, thus resulting in an age-dependent transmembrane signaling disorder. Therefore, further understanding of age-dependent disturbances of ICAM-1 regulation during inflammation can provide important clues as to appropriate targets for therapeutic interventions and prevention of vascular disorders in elderly at the level of the endothelial surface membrane. (c) 2006 Elsevier Ireland Ltd. All rights reserved.