dc.contributor.author | Zarkada, Georgia | |
dc.contributor.author | Chen, Xun | |
dc.contributor.author | Zhou, Xuetong | |
dc.contributor.author | Lange, Martin | |
dc.contributor.author | Zeng, Lei | |
dc.contributor.author | Lv, Wenyu | |
dc.contributor.author | Zhang, Xuan | |
dc.contributor.author | Li, Yunhua | |
dc.contributor.author | Zhou, Weibin | |
dc.contributor.author | Liu, Keli | |
dc.contributor.author | Chen, Dongying | |
dc.contributor.author | Ricard, Nicolas | |
dc.contributor.author | Liao, James | |
dc.contributor.author | Kim, Young-Bum | |
dc.contributor.author | Benedito, Rui | |
dc.contributor.author | Claesson-Welsh, Lena | |
dc.contributor.author | Alitalo, Kari | |
dc.contributor.author | Simons, Michael | |
dc.contributor.author | Ju, Rong | |
dc.contributor.author | Li, Xuri | |
dc.contributor.author | Eichmann, Anne | |
dc.contributor.author | Zhang, Feng | |
dc.date.accessioned | 2024-05-08T13:38:47Z | |
dc.date.available | 2024-05-08T13:38:47Z | |
dc.date.issued | 2023-08-04 | |
dc.identifier.citation | Circ Res. 2023 Aug 4;133(4):333-349. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/19308 | |
dc.description.abstract | 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), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction.
CONCLUSIONS
Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier. | es_ES |
dc.description.sponsorship | This project was supported by grants from National Key R&D Program of
China (2021YFA1101200), National Natural Science Foundation of China
(82070500, 82241009), Natural Science Foundation of Guangdong Province
(2022A1515012210), and the Science and Technology Program of Guangzhou
City (202102010183) to F. Zhang, and from National Institutes of Health (NIH;
1R01DK120373-01A1) and the Leducq Foundation (TNE ATTRACT) to A. Eichmann. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Lippincott Williams & Wilkins (LWW) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | Lymphatic Vessels | es_ES |
dc.subject.mesh | Monomeric GTP-Binding Proteins | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Vascular Endothelial Growth Factor A | es_ES |
dc.subject.mesh | Endothelial Cells | es_ES |
dc.subject.mesh | Phosphatidylinositol 3-Kinases | es_ES |
dc.subject.mesh | Chylomicrons | es_ES |
dc.subject.mesh | Capillary Permeability | es_ES |
dc.title | Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 37462027 | es_ES |
dc.format.volume | 133 | es_ES |
dc.format.number | 4 | es_ES |
dc.format.page | 333 | es_ES |
dc.identifier.doi | 10.1161/CIRCRESAHA.123.322607 | es_ES |
dc.contributor.funder | National Natural Science Foundation of China | es_ES |
dc.contributor.funder | Fondation Leducq | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1524-4571 | es_ES |
dc.relation.publisherversion | 10.1161/CIRCRESAHA.123.322607 | es_ES |
dc.identifier.journal | Circulation research | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Genética Molecular de la Angiogénesis | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |