Long-term regulation of endothelial junctions by inflammatory mediators
Endothelial cells regulate the passage of fluids, macromolecules, and cells from the blood stream to the surrounding tissues. Endothelial permeability and transendothelial migration (TEM) are critical during acute and chronic inflammation, shock, atherosclerosis, acute lung distress syndrome, and primary tumor growth and metastasis. The EC is not only centrally involved in this process, but also readily exposed to circulating drugs and humanized antibodies, thus making it a perfect target for novel drug development. Hence, it is essential to understand its mechanisms of regulation in order to design better therapeutic strategies. Endothelial intercellular adhesion, and thus permeability, is tightly regulated by a number of vasoactive factors and is critical to determine the onset and extent of an inflammatory response. The endothelial AJ is comprised of the classical cadherin VE-cadherin and the catenins p120, β-catenin and plakoglobin. ECs contain AJ complexes along the cell-cell border in close association with a cortical actin ring, supporting strong cell-cell adhesion and resistance to the shear stress induced by the blood flow.
Our previous work demonstrated that STAT3 phosphorylation leads to a sustained loss of barrier function in HUVEC. We continue to investigate the mechanisms regulating long-term (days) barrier loss downstream of IL-6 and STAT3. The lab is using several super-resolution strategies, including Airyscan and STED, and live tracking (mEOS2) in combination with AJ component mutants to better understand how the AJ forms and disassembles. The role for actin remodeling and focal adhesion components is being studied via live imaging of lifeact, Rho family sensors and Arp2/3 fusion proteins.