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    Area of Science:

    • Vascular Biology
    • Molecular Genetics
    • Developmental Biology

    Background:

    • Lymphatic malformations (LMs) result from genetic mutations affecting lymphatic vasculature.
    • Activating KRAS mutations are linked to LM complications like lymphedema and chylothorax.
    • The mechanism of valve loss in KRAS-mutated LMs remains unclear.

    Purpose of the Study:

    • To elucidate the molecular mechanisms underlying lymphatic valve loss in the context of KRAS mutations.
    • To investigate the role of KRAS signaling in lymphatic valve development and maintenance.

    Main Methods:

    • Utilized a mouse model with lymphatic-specific, inducible KRAS-G12D expression and a Prox1GFP reporter.
    • Analyzed human dermal lymphatic endothelial cells (hdLECs) with KRAS-G12D expression using molecular and biochemical assays.
    • Performed mechanistic studies in 3D collagen matrices and tested MMP inhibitors in vivo.

    Main Results:

    • Lymphatic KRAS-G12D expression impaired valve development in multiple tissues.
    • KRAS-G12D upregulated the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs) in hdLECs.
    • MMPs degraded the extracellular matrix (ECM) core of lymphatic valves, and MMP inhibition rescued valve development.

    Conclusions:

    • Hyperactive KRAS signaling drives LM pathogenesis by upregulating MMPs.
    • Excessive MMP activation, fueled by the PA pathway, leads to lymphatic valve ECM degradation.
    • This degradation mechanism prevents lymphatic valve formation, contributing to LM phenotypes.