title: MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling.
abstract: An accumulation of milk fat globule EGF-8 protein (MFG-E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG-E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30 months. In fresh and early passage VSMC isolated from old aortae, an increase in CDK4 and PCNA, an increase in the acceleration of cell cycle S and G2 phases, decrease in the G1/G0 phase, and an increase in PDGF and its receptors confer elevated proliferative capacity, compared to young VSMC. Increased coexpression and physical interaction of MFG-E8 and integrin αvβ5 occur with aging in both the rat aortic wall in vivo and in VSMC in vitro. In young VSMC in vitro, MFG-E8 added exogenously, or overexpressed endogenously, triggers phosphorylation of ERK1/2, augmented levels of PCNA and CDK4, increased BrdU incorporation, and promotes proliferation, via αvβ5 integrins. MFG-E8 silencing, or its receptor inhibition, or the blockade of ERK1/2 phosphorylation in these cells reduces PCNA and CDK4 levels and decelerates the cell cycle S phase, conferring a reduction in proliferative capacity. Collectively, these results indicate that MFG-E8 in a dose-dependent manner coordinates the expression of cell cycle molecules and facilitates VSMC proliferation via integrin/ERK1/2 signaling. Thus, an increase in MFG-E8 signaling is a mechanism of the age-associated increase in aortic VSMC proliferation.
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging-National Institutes of Health, Baltimore, MD 21224, USA. mingyiw@grc.nia.nih.gov
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.forename: Zongming
authors.initials: Z
authors.lastname: Fu
authors.forename: James
authors.initials: J
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Liqun
authors.initials: L
authors.lastname: Jiang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Khazan
authors.forename: Richard
authors.initials: R
authors.lastname: Telljohann
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Krug
authors.forename: Maria
authors.initials: M
authors.lastname: Pikilidou
authors.forename: Robert E
authors.initials: RE
authors.lastname: Monticone
authors.forename: Robert
authors.initials: R
authors.lastname: Wersto
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Eyk
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000367:Age Factors; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008894:Milk Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
chemical_list: D000954:Antigens, Surface; D016023:Integrins; C499941:MFGE8 protein, rat; D008894:Milk Proteins; D010982:Platelet-Derived Growth Factor