Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: upregulation of alpha2beta1 integrin and disassembly of actin filaments.
Fibroblast growth factor-2 (FGF-2) has been implicated in vascular smooth muscle cell (SMC) migration, a key process in vascular disease. We demonstrate here that FGF-2 promotes SMC motility by altering beta1 integrin-mediated interactions with the extracellular matrix (ECM). FGF-2 significantly increased surface expression of alpha2beta1, alpha3beta1, and alpha5beta1 integrins on human SMCs, as assessed by flow cytometry. The greatest increase was for the collagen-binding alpha2beta1 integrin. Despite this, FGF-2 did not increase SMC adhesion to type I collagen but instead promoted SMC elongation and SMC motility. The latter was evaluated by using a microchemotaxis chamber and by digital time-lapse video microscopy. Although FGF-2 was not chemotactic for human SMCs, cells preincubated with FGF-2 displayed a 3.1-fold increase in migration to the undersurface of porous type I collagen-coated membranes and a 2.1-fold increase in migration speed on collagen. Furthermore, chemotaxis to platelet-derived growth factor-BB on collagen was significantly greater in SMCs exposed to FGF-2. FGF-2-induced elongation and migration on collagen were inhibited by a blocking anti-alpha2beta1 antibody; however, SMC adhesion to collagen was unaffected. SMC migration on fibronectin was also enhanced by FGF-2, although less prominently: migration through porous membranes increased 1.8-fold, and migration speed increased 1.3-fold. Also, FGF-2 completely disassembled the smooth muscle alpha-actin-containing stress fiber network contemporaneously with the change in integrin expression and cell shape. We conclude that (1) exogenous FGF-2 promotes SMC migration and potentiates chemotaxis to PDGF-BB; (2) the promigratory effect of FGF-2 is especially prominent on type I collagen and is mediated by upregulation of alpha2beta1 integrin; and (3) FGF-2 disassembles actin stress fibers, which may promote differential utilization of alpha2beta1 integrin for motility but not adhesion. This dynamic SMC-ECM interplay may be an important mechanism by which FGF-2 facilitates SMC motility in vivo.
Pickering
J G
JG
Department of Medicine (Cardiology), University of Western Ontario, London, Canada. gpickrng@rri.uwo.ca
Uniyal
S
S
Ford
C M
CM
Chau
T
T
Laurin
M A
MA
Chow
L H
LH
Ellis
C G
CG
Fish
J
J
Chan
B M
BM
D008841:Actin Cytoskeleton; D000199:Actins / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D002465:Cell Movement; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D051381:Rats; D038981:Receptors, Collagen; D015854:Up-Regulation
D000199:Actins; D016023:Integrins; D010982:Platelet-Derived Growth Factor; D038981:Receptors, Collagen; D016222:Fibroblast Growth Factor 2; D003094:Collagen