title: Microfibrils and fibrillin-1 induce integrin-mediated signaling, proliferation and migration in human endothelial cells.
abstract: Microfibrils are macromolecular complexes associated with elastin to form elastic fibers that endow extensible tissues, such as arteries, lungs, and skin, with elasticity property. Fibrillin-1, the main component of microfibrils, is a 350-kDa glycoprotein for which genetic haploinsufficiency in humans can lead to Marfan syndrome, a severe polyfeatured pathology including aortic aneurysms and dissections. Microfibrils and fibrillin-1 fragments mediate adhesion of several cell types, including endothelial cells, while fibrillin-1 additionally triggers lung and mesangial cell migration. However, fibrillin-1-induced intracellular signaling is unknown. We have studied the signaling events induced in human umbilical venous endothelial cells (HUVECs) by aortic microfibrils as well as recombinant fibrillin-1 Arg-Gly-Asp (RGD)-containing fragments PF9 and PF14. Aortic microfibrils and PF14, not PF9, substantially and dose dependently increased HUVEC cytoplasmic and nuclear calcium levels measured using the fluorescent dye Fluo-3. This effect of PF14 was confirmed in bovine aortic endothelial cells. PF14 action in HUVECs was mediated by αvβ3 and α5β1 integrins, phospholipase-C, inosital 1,4,5-trisphosphate, and mobilization of intracellular calcium stores, whereas membrane calcium channels were not or only slightly implicated, as shown in patch-clamp experiments. Finally, PF14 enhanced endothelial cell proliferation and migration. Hence, fibrillin-1 sequences may physiologically activate endothelial cells. Genetic fibrillin-1 deficiency could alter normal endothelial signaling and, since endothelium dysfunction is an important contributor to Marfan syndrome, participate in the arterial anomalies associated with this developmental disease.
authors.affiliation: Laboratoire Physiopathologies Vasculaires, Interactions Cellulaires, Signalisation et Vieillissement, Université Joseph Fourier, CEA, Institut National de Santé et de Recherche Médicale, U882, Grenoble, France.
authors.forename: Boubacar
authors.initials: B
authors.lastname: Mariko
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Ghandour
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Raveaud
authors.forename: Mickaël
authors.initials: M
authors.lastname: Quentin
authors.forename: Yves
authors.initials: Y
authors.lastname: Usson
authors.forename: Jean
authors.initials: J
authors.lastname: Verdetti
authors.forename: Philippe
authors.initials: P
authors.lastname: Huber
authors.forename: Cay
authors.initials: C
authors.lastname: Kielty
authors.forename: Gilles
authors.initials: G
authors.lastname: Faury
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020894:Microfibrils / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology*; D054392:Adipokines
chemical_list: D002118:Calcium; D000071838:Fibrillin-1; D000071837:Fibrillins; D039482:Integrin alpha5; D039564:Integrin alphaV; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines