An alteration in vascular permeability is a defining feature of diverse processes including arteriosclerosis,inflammation, acute lung injury (ALI) and angiogenesis. In contrast, there is little known about processes thatdetermine barrier protection or barrier restoration after edemagenic agents. We have previously shown thathepatocyte growth factor (HGF) binding to its cell surface receptor tyrosine kinase, c-Met, promotes increasedEC barrier function via cytoskeletal rearrangement and attenuates inflammatory lung edema formation.Our data indicate that HGF promotes c-Met recruitment into specialized caveolin-1-enriched plasmamembrane microdomains known as lipid rafts and transactivates sphingosine 1-phosphate receptor (S1P1)and CD44 (a major hyaluronan glycoprotein receptor) within these lipid raft structures. We have identifiedseveral potential regulators of HGF/c-Met-induced actin cytoskeletal rearrangement and consequent ECbarrier enhancement in lipid rafts including the Rac1 exchange factor, Tiaml, the vesicle regulatory protein,dynamin 2, myosin light chain kinase (MLCK) and paxillin. Further, genes encoding c-Met and paxillincontain coding single nucleotide polymorphisms (SNPs) which potentially alter function and lead to increasedsusceptibility to ALI.
Specific Aim #1 will identify the role of these SNPs in HGF/c-Met signaling from lipidrafts to the actin cytoskeleton and consequent human EC barrier regulation. Our preliminary data in murinemodel of lipopolysaccharide (LPS)-induced pulmonary vascular hyper-permeability suggests that caveolin-1regulates HGF-mediated vascular integrity in vivo.
Specific Aim #2 will define HGF/c-Met/caveolin-1interactions in the regulation of endothelial cortical actin formation, tension and lung permeability. Further,our published data indicates that HGF/c-Met transactivation of the S1P1 is crucial for its EC barrierenhancingproperties. Thus, to explore growth factor transactivation in regulating EC barrier function,Specific Aim #3 will identify HGF/c-Met/S1P1 interactions in the regulation of endothelial cortical actinformation, tension and lung permeability.
Specific Aim #4 will define HGF/c-Met/CD44 interactions in theregulation of endothelial cortical actin formation, tension and lung permeability. Increased understanding ofHGF/c-Met-mediated signal transduction and EC barrier regulation from lipid rafts may provide noveltherapies for a variety of disease processes involving defects in EC barrier regulation.
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