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PubMed2005

Seeing ghosts: the effect of unsampled populations on migration rates estimated for sampled populations.

In 2004, the term 'ghost population' was introduced to summarize the effect of unsampled subpopulations that exchange migrants with other subpopulations that have been sampled. Estimated long-term migration rates among populations sampled will be affected by ghost populations. Although it would be convenient to be able to define an apparent migration matrix among sampled populations that incorporate the exchange of migrants with ghost populations, no such matrix can be defined in a way that predicts all features of the coalescent process for the true migration matrix. This paper shows that if the underlying migration matrix is symmetric, it is possible to define an apparent migration matrix among sampled subpopulations that predicts the same within-population and between-population homozygosities among sampled populations as is predicted by the true migration matrix. Application of this method shows that there is no simple relationship between true and apparent migration rates, nor is there a way to place an upper bound on the effect of ghost populations. In general, ghost populations can create the appearance of migration between subpopulations that do not actually exchange migrants. Comparison with published results from the application of the program, MIGRATE, shows that the apparent migration rates inferred with that program in a three-subpopulation model differ from those based on pairwise homozygosities. The apparent migration matrix determined by the method described in this paper probably represents the upper bound on the effect of ghost populations.

Homozygote↗
PubMed2005

Involvement of filamin A and filamin A-interacting protein (FILIP) in controlling the start and cell shape of radially migrating cortical neurons.

Precisely regulated radial cell migration out of the ventricular zone is essential for corticogenesis. However, molecular mechanisms controlling the start of migration and the dynamics of migrating cell shape remain elusive. Here, we show novel mechanisms that can tether ventricular zone cells and control migrating cell shape. The novel protein Filamin A-interacting protein (FILIP) interacts with Filamin A, an indispensable actin-binding protein for cell motility, and induces its degradation in COS-7 cells. Degradation of Filamin A is indicated in the cortical ventricular zone where FILIP mRNA localizes. Furthermore, most ventricular zone cells that overexpress FILIP fail to migrate in explants. These results indicate that FILIP acts through a Filamin A-F-actin axis to control the start of neocortical cell migration from the ventricular zone. Filamin A also determines the shape of migrating neocortical neurons, which show global morphological changes and complicated behavior during that migration. Dysfunction of Filamin A, caused by a mutant Filamin A expression, prevents cells from acquiring consistent polarity toward specific direction and decreases motility in the subventricular and intermediate zones. In contrast, Filamin A overexpression, achieved by a short interfering RNA for FILIP, promotes the development and maintenance of a bipolar shape also in the subventricular and intermediate zones. These results suggest that the amount of Filamin A helps migrating neurons determine their mode of migration, multipolar or bipolar, prior to entering the cortical plate and that FILIP is responsible, at least in part, for the Filamin A content of migrating neurons.

Animals↗
PubMed2005

Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence-derived neurons.

Correct positioning of cortical neurons during development depends on the radial migration of the projection neurons and on the coordinated tangential and radial migrations of the subcortically generated interneurons. As previously shown, a transient and moderate maternal deficiency in thyroxin during early corticogenesis alters the radial migration of projection neurons. To determine if a similar effect might also affect tangential migration of medial ganglionic eminence (MGE)-derived neurons at the origin of cortical interneurons, explants of MGE from green fluorescent protein (GFP)-transgenic embryos were implanted into flat cortical mounts from wild-type embryos. The distances covered and the preferential migration (medially) of GFP-MGE neurons from embryos of hypothyroxinemic dams are not affected in their tangential migration into wild-type control cortices. In contrast, when GFP-MGE neurons from embryos of control or hypothyroxinemic dams migrate within cortices from embryos of hypothyroxinemic dams, the GFP-MGE-derived neurons lose their preferential direction of migration, although they still migrate for long distances throughout the cortex. Our results show that maternal hypothyroxinemia alters the tangential migration of GFP-MGE-derived neurons in the neocortex of the progeny and suggest that this alteration is not derived from the migratory neurons themselves but through undefined short- and long-range cues responsible for the guidance of their migration.

Animals↗
PubMed1995

Divalent cations (Mg2+, Ca2+) differentially influence the beta 1 integrin-mediated migration of human fibroblasts and keratinocytes to different extracellular matrix proteins.

Directed migration of keratinocytes and fibroblasts is a fundamental prerequisite in wound healing. Cation-dependent affinity changes of integrins are responsible for cell adhesion to and deadhesion from extracellular matrix proteins and have been implicated in driving cell migration. The specific requirements for divalent cations in the integrin-dependent migration of human dermal fibroblasts and human epidermal keratinocytes to various extracellular matrix proteins have been studied in vitro using blindwell Boyden chambers. The migration of the tested cells to collagen type I was mediated by the alpha 2 beta 1 integrins, to fibronectin by the combined action of the alpha 3 beta 1 and the alpha 5 beta 1 integrin, and the migration of fibroblasts to laminin dependent both on the alpha 2 beta 1 and the alpha 6 beta 1 integrins. No migration of keratinocytes to laminin was detected. Mg2+ alone induced cell migration with an optimum at 2 mM for fibroblasts and at 10 mM for keratinocytes. Ca2+ alone at 2 mM only marginally enhanced fibroblast and keratinocyte migration. At higher concentrations Ca2+ suppressed the stimulatory Mg2+ effect. 2 mM Ca2+ combined with 2 mM Mg2+ showed an additive stimulatory effect on the migration of fibroblasts to fibronectin. These data suggest that extracellular divalent cations differentially influence the integrin-mediated cell migration. A concentration gradient of Mg2+/Ca2+, as reported in tissue injury, thus may play a regulatory role in cell migration required for tissue remodelling.

Cations, Divalent↗
PubMed1996

Effects of extracellular matrix molecules on subepidermal neural crest cell migration in wild type and white mutant (dd) axolotl embryos.

Migration of neural crest (NC) derived pigment cells is restricted in the white mutant (dd) axolotl embryo (Ambystoma mexicanum). Transplantations between mutant and wild type embryos show that the extracellular matrix (ECM) of the white mutant is unable to support the migration of prospective pigment cells in wild type embryos (Löfberg et al., 1989, Dev. Biol. 131:168-181). In the present study, we test the effects of various purified ECM molecules on NC cell migration in the subepidermal migratory pathway of wild type (D/-) and white mutant (dd) axolotl embryos. We adsorbed the ECM molecules onto membrane microcarriers, which were then implanted under the epidermis. Fibronectin (FN), tenascin (TN), collagens I and VI, and a chick aggrecan stimulated migration in both types of embryos. Laminin-nidogen, rat chondrosarcoma aggrecan, and shark aggrecan stimulated migration in dd embryos but did not affect migration in D/- embryos. Collagen III, fibromodulin and bovine aggrecan had no effect on migration in either type of embryo. NC cells did not migrate on control microcarriers, which lacked ECM molecules. Some cells observed contacting, and presumably migrating on, coated microcarriers could be identified as pigment cells by their ultrastructure. Enzymatic digestion in vivo with chondroitinase ABC had no effect on NC cell migration. The neutral or stimulatory effect of the aggrecans is surprising; when tested in vitro they inhibited NC cell migration. The effect of three-dimensionality and other molecules present either in the embryonic ECM or in solution may overcome the inhibitory effect of aggrecans.

Ambystoma↗
PubMed1995

MCP-1-stimulated monocytes preferentially utilize beta 2-integrins to migrate on laminin and fibronectin.

Recruitment of monocytes to inflammatory sites involves a series of sequential attachments and detachments to extracellular matrix proteins in response to a chemoattractant gradient. In this study we compared the migration of human peripheral blood monocytes on different extracellular matrix proteins in response to monocyte chemoattractant protein-1 (MCP-1) and N-formylmethionyl-leucyl-phenylalanine. Monocytes migrated more effectively on laminin compared with other extracellular matrix proteins. In contrast, this preference was not observed with neutrophils, suggesting that the monocytes and neutrophils may have differences in their migration on extracellular matrix proteins. To study this further, function-blocking monoclonal antibodies were used to examine mechanistically whether beta 1- and beta 2-integrins were involved in monocyte migration on fibronectin or laminin in response to MCP-1. Monocyte migration on both laminin and fibronectin was blocked 100% (P < 0.05) by intact monoclonal antibody, F(ab') fragments, and F(ab')2 fragments to beta 2-integrins. We also determined that antibodies to beta 2-integrins block monocyte migration that has already been initiated. In contrast, antibody to the beta 1-integrins inhibited monocyte migration by approximately 40% (P < 0.05). Thus monocytes that express both beta 1- and beta 2-integrins require utilization of beta 2-integrins in migration on extracellular matrix proteins. The results also suggest that beta 1-integrins facilitate monocyte migration but that monocyte migration is not absolutely dependent on the interaction of beta 1-integrins with extracellular matrix proteins. In contrast, neutrophil migration is beta 2-integrin dependent and is not facilitated by beta 1-integrins.

CD18 Antigens↗
PubMed1992

Migration of IEC-6 cells: a model for mucosal healing.

Cell migration is the principal force behind the early restitution of erosions of the mucosa of the gastrointestinal tract. Despite the importance of cell migration to healing, no attempts to study the process in culture have been reported. We have attempted to standardize conditions for migration and test the migration responses of the small intestinal epithelial crypt cell line IEC-6 in some experimental situations already well known in vivo. We found good correspondence between in culture and in vivo on the following points: 1) migration was independent of DNA synthesis; 2) DNA synthesis was not concentrated at the wound edge; and 3) inhibition of actin polymerization stopped migration altogether. In addition, the presence of an extracellular matrix maximized migration. Protein inhibitors with different modes of action inhibited cell migration to different degrees, not always commensurate with their inhibition of protein synthesis. Cell surface proteoglycans were important; hyaluronic acid had an effect, but the secretion of a migration-stimulating substance by wounded cells was equivocal. Significantly, alpha-difluoromethylornithine (DFMO), which inhibits ornithine decarboxylase and polyamine synthesis, almost totally prevented cell migration. Because DFMO also prevents healing of mucosal erosions in vivo, we believe that this model can be used, keeping in mind its spatial limitations, to study the process of cell migration involved in the early restitution of mucosal erosions.

Cell Communication↗
PubMed1999

Effects of growth factors and trefoil peptides on migration and replication in primary oxyntic cultures.

Restitution, the lateral migration of cells over an intact basement membrane, maintains mucosal integrity. We studied the regulation of migration and proliferation of enzyme-dispersed canine oxyntic mucosa cells in primary culture. Confluent monolayers were wounded and cultured in serum-free medium, and cells migrating into the wound were counted. [3H]thymidine incorporation into DNA was studied using subconfluent cultures. Considerable migration occurred in untreated monolayers; however, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, basic fibroblast growth factor (bFGF), insulin-like growth factor I (IGF-I), two trefoil peptides, and interleukin (IL)-1beta further enhanced migration. The specific EGF receptor (EGFR) monoclonal antibody, MAb-528, inhibited both basal and TGF-alpha- or IL-1beta-stimulated migration, but not the response to trefoil peptide, bFGF, or IGF-I. Exogenous TGF-beta inhibited cell proliferation but did not alter migration. Immunoneutralization with anti-TGF-beta blocked the response to exogenous TGF-beta and produced a small enhancement of basal thymidine incorporation but did not attenuate basal or TGF-alpha-stimulated migration. In conclusion, endogenous EGFR ligands regulate proliferation and migration. TGF-beta inhibits mitogenesis; it did not upregulate migration in these cultures. Although bFGF, IGF-I, and IL-1beta enhance gastric epithelial migration, only IL-1beta acted in a TGF-alpha-dependent fashion.

Animals↗
PubMed1992

Human tracheobronchial epithelial cells direct migration of lung fibroblasts in three-dimensional collagen gels.

Normal airway morphogenesis and repair after injury depend in part on the interaction between the mesenchymal and epithelial cells in the tracheobronchial tree. We cultured human lung fibroblasts between layers of type I collagen gel and examined sections through these three-dimensional matrices to assess fibroblast migration. The migration assay used in these experiments allowed simultaneous assessment of directed and random fibroblast migration as well as cell number. We tested the hypothesis that human tracheobronchial epithelial (HTBE) cells direct the migration of fibroblasts. When fibroblasts were cultured alone, migration was nearly equivalent in the upper and lower collagen layers. When HTBE cells were plated on the upper collagen lattice, there was a net migration of fibroblasts toward the HTBE cells. The differential migration was evident early in culture but became maximal after 1 wk. Differences increased at higher HTBE cell inoculation densities. No epithelial chemokinetic or mitogenic influence was evident: total cell migration and total fibroblast number were not significantly different between the control and coculture sections. HTBE fibronectin production may contribute to directed migration because fibronectin, added to the upper lattice, reproduced a portion of the directed migration seen in coculture. Our data support the hypothesis that epithelial cells direct fibroblast migration.

Bronchi↗
PubMed1997

Integrin mediation of alveolar epithelial cell migration on fibronectin and type I collagen.

Acute lung injury leads to type I alveolar epithelial cell (AEC) death, denudation of the alveolar basement membrane, and formation of an alveolar provisional matrix from fibronectin, fibrinogen, and type I collagen. The provisional matrix provides a scaffold for alveolar repair. To restore normal lung architecture, surviving type II AECs must reepithelialize denuded alveoli. We examined whether AECs migrate on provisional matrix proteins and whether integrins mediate this migration using a Boyden chemotaxis chamber. Cultured AECs migrated on fibronectin-coated filters by haptotaxis (defined as movement on a solid-phase substrate) more than one type I collagen-coated filters, and they did not migrate on fibrinogen-coated filters. Soluble fibronectin augmented migration on type I collagen-coated filters, but not on fibronectin-coated filters. Anti-alpha v beta 3-integrin monoclonal antibody (MAb) inhibited migration on substrate-bound fibronectin by 62-77%, whereas anti-beta 1-integrin MAb inhibited migration by 48%. Anti-alpha 2-integrin MAb almost completely inhibited migration on substrate-bound type I collagen, but not on fibronectin. The novel findings in this study are as follows: 1) AECs migrate by haptotaxis more effectively on substrate-bound fibronectin than on type I collagen; 2) alpha v beta 3- and beta 1-integrins partially mediate AEC haptotaxis on fibronectin; and 3) the alpha 2 beta 1-integrin mediates AEC migration on type I collagen. These results support the importance of type II cell migration on provisional matrix proteins during repair of lung injury.

Animals↗
PubMed1995

Effects of prostaglandin E2 on mesangial cell migration.

Mesangial cell migration is a feature of certain renal diseases such as mesangiocapillary glomerulonephritis, a disorder which responds to treatment with cyclo-oxygenase inhibitors. We undertook the present study to determine whether prostaglandin E2 (PGE2) might have a direct effect on mesangial cell migration. PGE2 (10(-8) M) treated cells migrated a mean percent area of 16.8 +/- 0.5 during 24 h when compared to control cells which migrated only a mean percent area of 10.3 +/- 0.8 (p < 0.001). At 48 h, PGE2-treated cells migrated a mean percent area of 21.7 +/- 1.1 when compared to control cells which migrated only a mean percent area of 14.7 +/- 1.4 (p < 0.01). Meclofenamate (10(-5) M), a cyclo-oxygenase inhibitor, significantly (p < 0.02) inhibited migration of mesangial cells (at 48 h controls 13.4 +/- 0.5 vs. meclofenamate-treated cells 3.2 +/- 0.8). Since meclofenamate attenuates basal production of PGE2 by mesangial cells, inhibition of migration by mesangial cells by meclofenamate indicates that the basal production of PGE2 by mesangial cells also significantly contributes to the migration of mesangial cells. 3-Isobutyl-1-methylxanthine (IBMX, 10(-3) M), a phosphodiesterase inhibitor, also significantly (p < 0.001) enhanced migration of mesangial cells (controls 13.4 +/- 0.5 vs. IBMX-treated cells 20.8 +/- 0.5). These results suggest that mesangial cell migration is directly enhanced by PGE2. The present study provides a rationale for the use of cyclo-oxygenase therapy in patients with mesangiocapillary glomerulonephritis.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Role of vascular cell adhesion molecule-1 and platelet-activating factor in selective eosinophil migration across vascular endothelial cells.

To determine the role of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in mediating selective eosinophil migration across vascular endothelial cells, we examined the effect of anti-ICAM-1 monoclonal antibody (mAb) and anti-VCAM-1 mAb on transendothelial migration of human eosinophils and neutrophils across IL-1- and IL-1-stimulated cultured vascular endothelial cells. We also studied the effect of a selective antagonist for platelet-activating factor (PAF) on the transendothelial migration of eosinophils and neutrophils. Transendothelial migration of eosinophils was increased by stimulation of the endothelial cells with IL-1 and IL-4, the latter of which has been shown to selectively induce VCAM-1 expression on the endothelial cells. On the other hand, neutrophil transendothelial migration was increased only by IL-1. Eosinophil migration across IL-4-stimulated endothelial cells was decreased by anti-ICAM-1 mAb and anti-VCAM-1 mAb. A selective PAF antagonist E6123 also decreased eosinophil migration across IL-4-stimulated endothelial cells. Eosinophil migration across IL-1-stimulated endothelial cells was also decreased by anti-ICAM-1 mAb and anti-VCAM-1 mAb in the presence of PAF antagonist. In contrast, neutrophil migration across IL-1-stimulated endothelial cells was decreased by anti-ICAM-1 mAb but not anti-VCAM-1 mAb. PAF antagonist alone or together with anti-VCAM-1 had no significant effect on IL-1-induced neutrophil transendothelial migration. These results indicate that VCAM-1 and PAF play an important role in mediating selective eosinophil migration across vascular endothelial cells.

Antibodies, Monoclonal↗
PubMed2004

cAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular smooth muscle cell migration.

OBJECTIVE: Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions such as atherosclerosis and restenosis after angioplasty. Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is a potent migration factor for VSMCs. cAMP-response element-binding protein (CREB) is the stimulus-induced transcription factor and activates transcription of target genes such as c-fos and interleukin-6. We examined whether CREB is involved in TNF-alpha-induced VSMC migration. METHODS AND RESULTS: TNF-alpha induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF-alpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF-alpha-induced CREB phosphorylation and c-fos mRNA expression. VSMC migration was evaluated using a Boyden chamber. Overexpression of dominant-negative form of CREB suppressed VSMC migration as well as Rac1 expression induced by TNF-alpha. Overexpression of dominant-negative Rac1 also inhibited TNF-alpha-induced VSMC migration. CONCLUSIONS: Our results suggest that p38-MAPK/CREB/Rac1 pathway plays a critical role in TNF-alpha-induced VSMC migration and may be a novel therapeutic target for vascular stenotic lesion. Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions. TNF-alpha, a potent migration factor for VSMCs, activated CREB through p38 mitogen-activated protein kinase (p38-MAPK). CREB inhibition suppressed TNF-alpha-induced VSMC migration and Rac1 expression. These results suggest p38-MAPK/CREB/Rac1 pathway mediates TNF-alpha-induced VSMC migration.

CREB-Binding Protein↗
PubMed1999

TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent.

-Migration of vascular smooth muscle cells (VSMC) is a key event in neointimal formation and atherosclerosis that may be linked to the accumulation of inflammatory cells and release of chemotactic cytokines. Tumor necrosis factor-alpha (TNF-alpha) induces chemotaxis of inflammatory cells and fibroblasts, but little is known about chemotactic signaling by TNF-alpha in VSMC. The aim of this study was to investigate the role of TNF-alpha in VSMC migration and to elucidate the chemotactic signaling pathways mediating this action. TNF-alpha (50 to 400 U/mL) induced migration of cultured rat aortic VSMC in a dose-dependent manner. Because activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) is known to be required in platelet-derived growth factor-directed and angiotensin II-directed migration of these cells, we used the MAPK-inhibitor PD98059 to determine if chemotactic signaling by TNF-alpha involves the MAPK pathway as well. We found that TNF-alpha-directed migration was substantially inhibited by PD98059. TNF-alpha (100 U/mL) transiently activated MAPK with a maximal induction 10 minutes after stimulation that returned to baseline levels by 2 hours after treatment. Only a single peak of increased MAPK activity was seen. PD98059 also blocked TNF-alpha-stimulated MAPK activation in a concentration-dependent manner, which is consistent with its inhibition of TNF-alpha-directed migration. To identify which TNF-alpha receptor is involved in TNF-alpha-induced MAPK activation, antibodies against the p55 TNF-alpha receptor-1 (TNF-R1) and the p75 TNF-alpha receptor-2 (TNF-R2) were used. VSMC express both receptors, but TNF-alpha-induced MAPK activation was inhibited only by the TNF-R1 antibody. The TNF-R2 antibody had no effect. Thiazolidinediones are known to inhibit TNF-alpha signaling in adipose tissue and attenuate platelet-derived growth factor-directed and angiotensin II-directed migration in VSMC. We therefore investigated the effects of the thiazolidinediones troglitazone (TRO) and rosiglitazone (RSG) on TNF-alpha-induced migration. Both TRO and RSG inhibited migration, but neither attenuated TNF-alpha-induced MAPK activation, indicating that their antimigration activity was exerted downstream of MAPK. These experiments provide the first evidence that early activation of MAPK is a crucial event in TNF-alpha-mediated signal transduction leading to VSMC migration. Moreover, inhibition of TNF-alpha-directed migration by the insulin sensitizers TRO and RSG underscores their potential as vasculoprotective agents.

Analysis of Variance↗
PubMed1989

Effect of platelet factors on migration of cultured bovine aortic endothelial and smooth muscle cells.

Endothelial cell (EC) injury and the response of EC and smooth muscle cells (SMCs) to injury contribute to the pathophysiology in patients with vascular disease and atherosclerosis. Since platelets have been suggested to play an important role in modulating vascular injury, the present study was undertaken to examine the influence and mechanism of action of individual platelet factors on bovine aortic EC and SMC migration using an in vitro wound assay system. Serotonin decreased EC proliferation and reduced EC migration 21 +/- 1% (p less than 0.005), which was attenuated by imipramine. Transforming growth factor-beta reduced EC proliferation and decreased EC migration 52 +/- 3% (p less than 0.005). Norepinephrine increased EC proliferation but decreased EC migration 26 +/- 2% (p less than 0.005), which was abolished by phenoxybenzamine. Histamine increased EC proliferation but reduced EC migration 29 +/- 2% (p less than 0.005), which was attenuated by diphenhydramine. Platelet-derived growth factor decreased EC proliferation and decreased EC migration 40 +/- 2% (p less than 0.005). In contrast, serotonin increased SMC proliferation and increased SMC migration 31 +/- 2% (p less than 0.005), which was abolished by ketanserin. Transforming growth factor-beta increased SMC migration 35 +/- 5% (p less than 0.005). Norepinephrine increased SMC proliferation and increased SMC migration 43 +/- 4% (p less than 0.005), which was abolished by propranolol. Histamine increased SMC proliferation and increased SMC migration 38 +/- 3% (p less than 0.005), which was abolished by cimetidine. Platelet-derived growth factor increased SMC proliferation and increased SMC migration 40 +/- 3% (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation.

The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel. In vivo, VSMCs are surrounded by and embedded in a variety of extracellular matrices (ECMs) that must be traversed during migration. One of the principal barriers to cell movement in the intact vessel is the basement membrane (BM) that surrounds each VSMC and separates the VSMC-containing medial cell layer from the endothelium. We have used a Boyden chamber to monitor the ability of VSMCs to degrade a BM barrier as they migrate toward a chemoattractant and to define the role of extracellular proteases in this process. We show that cultured VSMCs can migrate across a BM barrier and that this ability was dependent on the phenotypic state of the cell. VSMCs maintained in a proliferating or "synthetic" state readily migrated across a BM toward a chemoattractant, whereas the migration of serum-starved/differentiated VSMCs was suppressed by > 80% (P < .001). By use of a number of peptides that inhibit matrix metalloproteinase (MMP) activity, the migration of proliferating VSMCs across the BM barrier was inhibited by > 80% (P < .0001), whereas migration that occurred in the absence of the barrier was unaffected. Northern blotting and zymographic analyses indicated that 72-kD type IV collagenase (MMP2) was the principal MMP expressed and secreted by these cells. Accordingly, antisera capable of selectively neutralizing MMP2 activity also inhibited VSMC migration across the barrier without significantly affecting the migration of VSMCs in the absence of the barrier. Finally, MMP2 activity was also regulated by the phenotypic state of the cells in that MMP2 activity expressed by serum-starved/differentiated VSMCs was < 5% of that measured in proliferating VSMCs. Extrapolating to the in vivo situation in which VSMCs reside in an ECM composed of various BM barriers, these results suggest that VSMC migration in vivo may be dependent on MMP2 activity. That activity, in turn, could be regulated by the phenotypic state of VSMCs and increase as these cells undergo the transition from a quiescent and differentiated state to that of a dedifferentiated, proliferating, and motile phenotype after injury to the vessel.

Animals↗
PubMed1996

Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells.

Augmentation of nitric oxide (NO) production in vivo decreases lesions in a variety of models of arterial injury, and inhibition of NO synthase exacerbates experimental intimal lesions. Both vascular smooth muscle cell (VSMC) proliferation and migration contribute to lesion formation. Although NO inhibits VSMC proliferation, its effects on VSMC migration are unknown. To test the hypothesis that NO inhibits VSMC migration independent of inhibition of proliferation, we examined migration of rat aortic VSMCs after wounding of a confluent culture in the presence of chemical donors of NO. Hydroxyurea was used to eliminate any confounding effect of NO on proliferation. Three NO donors, diethylamine NONOate, spermine NONOate, and S-nitrosoglutathione, exhibited concentration-dependent inhibition of both number of migrating VSMCs and maximal distance migrated. Inhibition of migration was also seen with 8-Br-cGMP, suggesting that activation of guanylate cyclase may play a role in mediating the antimigratory effects of NO. Migration resumed after removal of NO donors, as evidenced by an increase in distance migrated. Measurement of VSMC protein synthesis and mitochondrial respiration indicated that inhibition of migration by NO donors was not due to metabolic cytostasis. These findings indicate that NO reversibly inhibits VSMC migration independent of proliferation or cytotoxicity, a novel mechanism by which both endogenous and pharmacological NO may alter vascular pathology.

Animals↗
PubMed1997

Cytokine-induced neutrophil transepithelial migration is dependent upon epithelial orientation.

The mechanisms by which mediators and cytokines stimulate neutrophils to migrate across the lung epithelium are still unclear. We hypothesized that neutrophil transepithelial migration depends upon polarity of the epithelium. We therefore compared neutrophil migration through human lung Type II-like alveolar epithelial cell line (A549) monolayers grown on the upper versus lower surface of permeable filters to simulate apical-to-basal and basal-to-apical movement of neutrophils, respectively. The classic chemoattractants formyl-methionylleucylphenylalanine (FMLP), leukotriene B4 (LTB4), and interleukin-8 (IL-8) induced equivalent neutrophil transepithelial migration in the apical-to-basal and basal-to-apical directions. However, the degree of neutrophil transepithelial migration was significantly greater in the basal-to-apical direction in response to either IL-1beta or tumor necrosis factor-alpha (TNF-alpha). Enhanced TNF-alpha-induced neutrophil migration through A549 monolayers in the basal-to-apical direction occurred regardless of whether the TNF-alpha was above or below the filter/monolayer complex. Actinomycin D pretreatment of A549 monolayers had no effect on FMLP-induced neutrophil transepithelial migration, but markedly (about 75%) inhibited both TNF-alpha- and IL-1beta-induced neutrophil transepithelial migration, regardless of monolayer orientation. Thus, in contrast to classic chemoattractants, IL-1beta and TNF-alpha induced greater neutrophil transepithelial migration in a basal-to-apical direction, and this occurred independently of the cytokine location, but depended upon intact metabolic capacity of the A549 cells. These data suggest that the mechanisms important for neutrophil transepithelial migration in response to classic chemoattractants differ from those important for migration in response to inflammatory cytokines.

Cell Line↗