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Endothelial Focal Adhesion Kinase Transcriptionally Regulates S1P1 to Maintain Lung Vascular Barrier Function
Author(s) -
Yazbeck Pascal,
Mehta Dolly
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.625.4
Subject(s) - focal adhesion , microbiology and biotechnology , barrier function , lung , endothelium , sphingosine kinase 1 , vascular permeability , pulmonary edema , receptor , biology , medicine , signal transduction , cancer research , pathology , sphingosine , sphingosine 1 phosphate
Formation of leaky blood vessels remains a persistent pathology in several diseases including acute lung injury. We recently demonstrated that focal adhesion kinase (FAK), a non‐receptor tyrosine kinase, canonically known to regulate focal adhesion formation plays a fundamental role in forming stable vasculature in adult mice lungs. We showed using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), that loss of EC‐FAK spontaneously destabilized vessel formation in adult mice leading to diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung mimicking acute lung injury (ALI). Sphingosine‐1‐phosphate (S1P) is a lipid mediator well known for its ability to strengthen endothelial barrier function. S1P binding to the S1P1 receptor is predominantly responsible for its barrier strengthening effect. Intriguingly, my Preliminary Data showed that S1P1 expression at the level of mRNA and protein was markedly suppressed in FAK depleted human and mouse lung ECs. I also found that KLF2 (Krϋppel‐like transcription factor 2) mRNA, which may regulate S1P1 expression, was reduced in FAK depleted cells. Based on these key findings I will address the innovative concept that FAK regulates the formation of stable endothelial barrier function by inducing S1P1 expression through KLF2 and thereby facilitate in maintaining normal vascular homeostasis following lung injury. I believe that by testing this hypothesis I will identify a novel paradigm of restoring the formation of stable endothelial barrier following lung injury potentially leading to development of novel therapeutics against ALI.