Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that protect vascular integrity have important therapeutic implications both in vivo and in vitro. We have previously shown that the binding of hepatocyte growth factor (HGF) to its cell surface receptor, c-Met, promotes Rac1-dependent increases in lung EC barrier function. Further examination of the regulatory mechanisms of HGF/c-Met-induced EC barrier enhancement revealed that HGF (25 ng/mL) promotes c-Met recruitment into specialized caveolin 1-enriched plasma membrane microdomains (lipid rafts). Abolishing lipid raft formation (MβCD) attenuated HGF-induced EC barrier enhancement. Within lipid rafts, HGF induced c-Met association with CD44 (a major glycoprotein receptor for hyaluronan). Silencing CD44 expression (siRNA) inhibited HGF-induced c-Met and Tiam1 (a Rac1 guanine nucleotide exchange factor) recruitment to lipid rafts, as well as the association of cortactin (an actin-binding regulatory protein) with dynamin 2 (a vesicular regulatory protein) within lipid raft structures. Silencing of either Tiam1 or dynamin 2 blocked HGF-induced Rac1 activation, cortactin recruitment to lipid rafts, and EC barrier enhancement. Silencing cortactin attenuated HGF-induced EC barrier regulation. Finally, HGF-mediated in vivo protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was inhibited in CD44 knockout mice. Taken together, these results suggest that lipid rafts are an essential regulator of HGF/c-Met-mediated barrier enhancement via a process involving CD44, Tiam1, Rac1, dynamin 2, and cortactin.
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