Fibroblast Growth Factor-2 Potentiates Vascular Smooth Muscle Cell Migration to Platelet-Derived Growth Factor

Abstract

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.

Nitric Oxide and C-Type Atrial Natriuretic Peptide Stimulate Primary Aortic Smooth Muscle Cell Migration via a cGMP-Dependent Mechanism

“…35,45 Similarly, actin stress fiber disassembly has been associated with increased migration in vascular smooth muscle cells. 36,37,46 NO was also shown to decrease cell adhesion in cultured mesangial cells, 47 and a preliminary experiment indicates the existence of a similar effect in primary aortic smooth muscle cell cultures. We therefore speculate that NO-induced cytoskeletal rearrangements may be causally related to increased cell migration in a model of primary aortic smooth muscle cells.…”

“…Reduced cell spreading and actin filament dissociation is associated with increased cell migration in both vascular smooth muscle cells and fibroblasts. [35][36][37] We therefore determined the effect of SNAP on cell morphology and actin filament organization. As shown in Figure 11, SNAP elicited cell rounding, an effect that was antagonized by the guanyl cyclase inhibitor ODQ, consistent with a cGMP-mediated mechanism associated with cell migration.…”

Role of FGFR signaling in the morphogenesis of the Drosophila visceral musculature

“…It has been shown in vertebrates that FGFR1 orchestrates the epithelial to mesenchymal transition of mesoderm at the primitive streak by down-regulating E-cadherin expression (Ciruna and Rossant, 2001). In migrating vascular smooth muscle cells, FGF-2 promotes motility by increasing expression of alpha2beta1 integrin (Pickering et al, 1997). Aside from controlling adhesion molecules, FGFR signaling could affect cell movement by modulating the dynamics of the cytoskeleton.…”

“…Vertebrate FGFR1 orchestrates the epithelial-to-mesenchymal transition of mesoderm at the primitive streak by down-regulating E-cadherin expression (Ciruna and Rossant, 2001). Furthermore, in migrating vascular smooth muscle cells, FGF-2 pro-motes motility by increasing expression of alpha2beta1 integrin, which in turn mediates contact between the cell membrane and collagen in the extracellular matrix (Pickering et al, 1997).…”

Intrinsic directionality of migrating vascular smooth muscle cells is regulated by NAD+ biosynthesis

“…Signal gradients in the local environment are important in this regard, with gradients of PDGF-BB being particularly so for vascular SMCs (Ferns et al, 1991;Pickering et al, 1997). However, it has recently been recognized that, in addition to external cues, there are intrinsic cellular attributes that determine whether a cell maintains a direct path of translocation or follows a more meandering route (Petrie et al, 2009).…”