EphA2 Activation Promotes the Endothelial Cell Inflammatory Response

Abstract

Objective Endothelial cell activation results in altered cell-cell interactions with adjacent endothelial cells and with infiltrating leukocytes. Eph receptors and their ephrin ligands regulate cell-cell interactions during tissue remodeling, and multiple proinflammatory mediators induce endothelial EphA receptor and ephrinA ligand expression. Therefore, we sought to elucidate the role of EphA receptors and ephrinA ligands in endothelial cell activation and atherosclerosis. Methods and Results qRT-PCR screening for EphA/ephrinA expression in atherosclerosis-prone macrovascular endothelium identified EphA2, EphA4, and ephrinA1 as the dominant isoforms. Endothelial activation with oxidized LDL (oxLDL) and proinflammatory cytokines induced EphA2 and ephrinA1 expression and sustained EphA2 activation, whereas EphA4 expression was unaffected. Atherosclerotic plaques from mice and humans show enhanced EphA2 and ephrinA1 expression colocalizing in the endothelial cell layer. EphA2 activation with recombinant Fc-ephrinA1 induces proinflammatory gene expression (ex. VCAM-1, E-Selectin) and stimulates monocyte adhesion, while inhibiting EphA2 (siRNA, pharmacological inhibitors) abrogated both ephrinA1-induced and oxLDL-induced VCAM-1 expression. Conclusions The current data suggest that enhanced EphA2 signaling during endothelial cell activation perpetuates proinflammatory gene expression. Coupled with EphA2 expression in mouse and human atherosclerotic plaques, these data implicate EphA2 as a novel proinflammatory mediator and potential regulator of atherosclerotic plaque development.

EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling

“…Although originally identified as regulators of axon guidance, the Eph receptors are now known to play profound roles in diverse physiological processes, such as angiogenesis (formation of new blood vessels from pre-existing ones), bone morphogenesis, inflammatory host responses, neurodegenerative diseases, and cancer (2,3). The Eph receptors are unique among the RTKs, as their mechanism of activation is distinctly different and much more complex.…”

LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis

“…Human normal and atherosclerotic artery specimen: All human normal and atherosclerotic artery samples were collected as described previously following the protocols approved by the Institutional Review Boards (37). These samples were considered to be deemed nonhuman subjects, as they were postmortem samples.…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…Endothelial activation with oxidized low-density lipoprotein and proinflammatory cytokines resulted in induction of EphA2 and EphA1 with sustained EphA2 activation. This resulted in proinflammatory gene expression and VCAM-1 and E-selectin induction, and identified these ephrins as potential regulators of atherosclerotic plaque development [86]. Van Gils et al showed that EphB2 is upregulated under proatherosclerotic flow conditions and functions as a chemoattractant, increasing leukocyte migration in the absence of additional chemokines [83].…”