title: EMILIN1/α9β1 integrin interaction is crucial in lymphatic valve formation and maintenance.
abstract: Lymphatic vasculature plays a crucial role in the maintenance of tissue interstitial fluid balance. The role of functional collecting lymphatic vessels in lymph transport has been recently highlighted in pathologies leading to lymphedema, for which treatments are currently unavailable. Intraluminal valves are of paramount importance in this process. However, valve formation and maturation have not been entirely elucidated yet, in particular, the role played by the extracellular matrix (ECM). We hypothesized that EMILIN1, an ECM multidomain glycoprotein, regulates lymphatic valve formation and maintenance. Using a mouse knockout model, we show that in the absence of EMILIN1, mice exhibit defects in lymphatic valve structure and in lymph flow. By applying morphometric in vitro and in vivo functional assays, we conclude that this impaired phenotype depends on the lack of α9β1 integrin engagement, the specific lymphatic endothelial cell receptor for EMILIN1, and the ensuing derangement of cell proliferation and migration. Our data demonstrate a fundamental role for EMILIN1-integrin α9 interaction in lymphatic vasculature, especially in lymphatic valve formation and maintenance, and underline the importance of this ECM component in displaying a regulatory function in proliferation and acting as a "guiding" molecule in migration of lymphatic endothelial cells.
authors.affiliation: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano (PN), Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Danussi
authors.forename: Lisa
authors.initials: L
authors.lastname: Del Bel Belluz
authors.forename: Eliana
authors.initials: E
authors.lastname: Pivetta
authors.forename: Teresa Maria Elisa
authors.initials: TM
authors.lastname: Modica
authors.forename: Andres
authors.initials: A
authors.lastname: Muro
authors.forename: Bruna
authors.initials: B
authors.lastname: Wassermann
authors.forename: Roberto
authors.initials: R
authors.lastname: Doliana
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D016023:Integrins / Q000032:analysis / Q000378:metabolism*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060066:Protein Interaction Maps
chemical_list: D016023:Integrins; D008562:Membrane Glycoproteins; C030340:elastin microfibril interface located protein; C113256:integrin alpha 9 beta 1
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