Integrin Affinity Modulation Critically Regulates Atherogenic Endothelial Activation in vitro and in vivo

While vital to platelet and leukocyte adhesion, integrin activation9s role in adherent cells remains controversial. In endothelial cells, atheroprone hemodynamics and oxidized lipoproteins promote endothelial integrin activation in vitro, and integrin inhibitors reduce endothelial activation to these stimuli in vitro and in vivo. However, integrin activation9s importance to endothelial phenotype remains unknown. We now show that integrin activation-deficient endothelial cells (talin1 L325R) adhere and spread, suggesting that integrin activation is dispensable for endothelial cell adhesion. However, talin1 L325R endothelial cells fail to support integrin activation, fibronectin deposition, and proinflammatory responses to atheroprone hemodynamics and oxidized lipoproteins. Rescuing integrin activation in talin1 L325R cells partially restores fibronectin deposition, whereas NF-kB activation and maximal fibronectin deposition require both integrin activation and other integrin-independent signaling. Similarly, atheroprone hemodynamics fail to promote inflammation and macrophage recruitment in endothelial-specific talin1 L325R mice. These studies demonstrate a vital role for integrin activation in regulating endothelial phenotype.