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  • Jaldin-Fincati, J. R., Pereira, R. V. S., Bilan, P. J., & Klip, A. (2018). Insulin uptake and action in microvascular endothelial cells of lymphatic and blood origin. American Journal of Physiology. Endocrinology and Metabolism, 315(2), E204–E217. https://doi.org/10.1152/ajpendo.00008.2018

    Whereas the blood microvasculature constitutes a biological barrier to the action of blood-borne insulin on target tissues, the lymphatic microvasculature might act as a barrier to subcutaneously administrated insulin reaching the circulation. Here, we evaluate the interaction of insulin with primary microvascular endothelial cells of lymphatic [human dermal lymphatic endothelial cells (HDLEC)] and blood [human adipose microvascular endothelial cells (HAMEC)] origin, derived from human dermal and adipose tissues, respectively. HDLEC express higher levels of insulin receptor and signal in response to insulin as low as 2.5 nM, while HAMEC only activate signaling at 100 nM (a dose that blood vessels do not normally encounter). Low insulin acts specifically through the insulin receptor, while supraphysiological insulin acts through both the IR and insulin growth factor-1 receptor. At supraphysiological or injection site-compatible doses pertinent to lymphatic microvessels, insulin enters HAMEC and HDLEC via fluid-phase endocytosis. Conversely, at physiologically circulating doses (0.2 nM) pertinent to blood microvessels, insulin enters HAMEC through a receptor-mediated process requiring IR autophosphorylation but not downstream insulin signaling. At physiological doses, internalized insulin is barely degraded and is instead released intact to the extracellular medium. In conclusion, we document for the first time the mechanism of interaction of insulin with lymphatic endothelial cells, which may be relevant to insulin absorption during therapeutic injections. Furthermore, we describe distinct action and uptake routes for insulin at physiological and supraphysiological doses in blood microvascular endothelial cells, providing a potential explanation for previously conflicting studies on endothelial insulin uptake.

  • Tokarz, V. L., Pereira, R. V. S., Jaldin-Fincati, J. R., Mylvaganam, S., & Klip, A. (2023). Junctional integrity and directional mobility of lymphatic endothelial cell monolayers are disrupted by saturated fatty acids. Molecular Biology of the Cell, mbcE22080367. https://doi.org/10.1091/mbc.E22-08-0367

    The lymphatic circulation regulates transfer of tissue fluid and immune cells towards the venous circulation. While obesity impairs lymphatic vessel function, the contribution of lymphatic endothelial cells (LEC) to metabolic disease phenotypes is poorly understood. LEC of lymphatic microvessels are in direct contact with the interstitial fluid, whose composition changes during the development of obesity, markedly by increases in saturated fatty acids. Palmitate, the most prevalent saturated fatty acid in lymph and blood, is detrimental to metabolism and function of diverse tissues, but its impact on LEC function is relatively unknown. Here, palmitate (but not its unsaturated counterpart palmitoleate) destabilized adherens junctions in human microvascular LEC in culture, visualized as changes in VE-cadherin, ⍺-catenin, and β-catenin localization. Detachment of these proteins from cortical actin filaments was associated with abundant actomyosin stress fibers. The effects were Rho-associated protein kinase (ROCK)- and myosin-dependent, as inhibition with Y-27632 or blebbistatin, respectively, prevented stress fiber accumulation and preserved junctions. Without functional junctions, palmitate-treated LEC failed to directionally migrate to close wounds in 2-dimensions and failed to form endothelial tubes in 3-dimensions. A reorganization of the lymphatic endothelial actin cytoskeleton may contribute to lymphatic dysfunction in obesity and could be considered as a therapeutic target.

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Last update from database: 3/14/25, 8:40 AM (UTC)

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