Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption

作者：Georgia Zarkada, Xun Chen, Xuetong Zhou, Martin Lange, Lei Zeng, Wenyu Lv, Xuan Zhang, Yunhua Li, Weibin Zhou, Keli Liu, Dongying Chen, Nicolas Ricard, James K. Liao, Young‐Bum Kim, Rui Benedito, Lena Claesson‐Welsh, Kari Alitalo, Michael Simons, Rong Ju, Xuri Li, Anne Eichmann, Feng Zhang · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.123.322607 · 被引用次数：44 · 研究领域：Lymphatic System and Diseases、Lymphatic Disorders and Treatments、Cerebrospinal fluid and hydrocephalus

BACKGROUND: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood. METHODS: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries. RESULTS: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1),...