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(Circulation Research. 2007;101:651.)
© 2007 American Heart Association, Inc.

Editorials

7ß1 Integrin

Putting the Brakes on Smooth Muscle Cell Proliferation

Emily Wilson

From the Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, College Station.

Correspondence to Emily Wilson, PhD, Associate Professor, Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, College Station TX 77843-1114. E-mail emilyw{at}tamu.edu

See related article, pages 672–681

Key Words: phenotypic modulation • signal transduction • vascular injury • adhesion molecules

Modulation of smooth muscle cell (SMC) differentiation status is an important aspect of vascular development, normal differentiation and function, and pathogenesis of various diseases including atherosclerosis, hypertension, and aneurysms. SMCs are not terminally differentiated and possess the ability to change phenotype in response to local environmental cues. Thus, changes in the local environment contribute to the switching of SMCs from the normal contractile phenotype to more proliferative, synthetic phenotypes that are present in these diseases.^1,2 The molecular mechanisms regulating smooth muscle phenotypic modulation are only now beginning to be understood, and how input from the extracellular matrix impacts these changes is still an area of ongoing research. In the current issue of Circulation Research, Welser et al³ investigate the contribution of the laminin binding integrin 7ß1 to phenotypic modulation of SMCs.

Adhesion to specific extracellular matrix (ECM) proteins is known to modulate the phenotypic status of SMCs in culture, and altered expression of ECM proteins in vivo correlate with changes in the status of SMCs and with vascular pathologies such as hypertension and atherosclerosis.^4,5 Thyberg⁶ reviewed the contributions of various ECM molecules to smooth muscle status and reported that SMCs grown on fibronectin (and other transitional matrices) showed increased proliferation, whereas cells on laminin and other basement membrane proteins proliferated slower and expressed larger quantities of smooth muscle specific contractile proteins. In addition, we^7,8and others⁹ showed that the type of ECM influences the response of SMC to mechanical stimulation. The differences between these SMCs are thought to arise because of differential stimulation of specific integrins and modulation of signal transduction pathways that regulate growth and differentiation when the cells are in contact with different matrix proteins.

Most studies relating adhesion to activation of specific signaling events have relied on comparing the response of cells in suspension to cells that are adhered or using in peptide mimetics to block the adhesion to specific integrins.¹⁰ While these types of studies have been beneficial in our early understanding of the role of adhesion and integrin signaling, the complexity of these pathways has made it difficult to determine the specific contributions of integrin-mediated signaling to more complex situations seen in normal vascular function and to vascular pathologies. Thus, Welser et al³ initiated the current studies to understand the contributions of alpha 7 integrin to modulation of proliferation in smooth muscle cells.

Previously published data from the Burkin laboratory showed that loss of 7ß1 integrin resulted in SMC hyperplasia in adult animals and vascular defects and partial embryonic lethality during development.¹¹ The purpose of the current study was to begin to understand the mechanisms by which 7ß1 integrin contributed to these pathologies. In the current study, Welser et al³ show that loss of 7 integrin results in the activation of extracellular signal-regulated kinase (ERK) coupled with increased translocation of the activated kinase to the nucleus. The authors confirmed the role of this pathway in the observed changes in proliferation by showing that either inhibition of ERK with the pharmacological inhibitor, U0126, or forced expression of 7 integrin by adenoviral infection of 7 integrin–deficient SMCs inhibited proliferation and restored the differentiation status of the SMCs. These studies provide one potential mechanism by which adhesion to laminin may influence SMC phenotypic status and suggests a more prominent role for 7 integrin in vascular biology than previously appreciated.

How 7 integrin expression influences ERK activation status and hence cellular proliferation was not studied directly by Welser et al.³ These authors show that inhibition of ras by the farnesyl transferase inhibitor manumycin A reduced nuclear localization of ERK 1/2 in 7 integrin–deficient SMCs significantly suggesting that 7 integrin may modulate ERK activation through modulating ras-dependent activation of ERK. However, it is not known whether the effects of 7 integrin on this pathway are direct effects on this signaling pathway or if it is indirectly mediated by altered expression of other integrins that are positive modulators of ERK 1/2 activation and translocation. Further studies will be necessary to address these potential mechanisms.

Activation of ERK 1/2 and modulation of cell proliferation and migration is modulated by a number of integrins. Various integrin-mediated adhesion has been shown to influence signaling pathway leading to ERK 1/2 activation at 3 key loci: (1) activation of receptor tyrosine kinases, (2) transmission of the signal through the cytosolic kinase cascade, and (3) trafficking of activated ERK to the nucleus¹⁰ (See Figure). Key to these events is regulation of the cytoskelton reorganization and localization of the components of the cascade. The site of 7 integrin-dependent modulation of these pathways has not been previously addressed, and most of the previous studies of the involvement of other integrins have focused on activating events not inhibitory events. Thus, 7 and other laminin binding adhesion molecules may be important in inhibiting signals that lead to cell growth in normal arteries, and breakdown of the basement membrane and loss of this inhibitory signal release this inhibition in response to injury and allow for modulations of SMCs to proliferative phenotypes.

View larger version (26K): [in this window] [in a new window]   Figure. Schematic of potential sites of regulation of ERK 1/2 activity and translocation by 7ß1 integrin in vascular smooth muscle cells. Welser et al report that 7ß1 integrin inhibits smooth muscle growth and activation and nuclear translocation of the extracellular signal-regulated kinase (ERK 1/2). The potential sites of regulation may be through altered expression of other integrins that positively regulate ERK 1/2 activity, modulation of receptor tyrosine kinase activity, direct interactions with the signaling pathways that regulate activity, or through modulation of nuclear translocation.

Relatively few studies^11–14have investigated the function of 7 integrin in SMCs and in the vasculature in general. However, its role in striated muscle has been addressed more fully, and 7 integrin expression correlates with differentiation in these tissues and localizes to unique structures (eg, myotendonous junctions) of the muscle membrane.¹⁵ Specific signal transduction pathways that are modulated by its engagement have not been adequately addressed, but one potential pathway that could influence the activation and localization or ERK is the interaction of 7 integrin with four-and-a half lim domain 2 (FHL2) protein.¹⁶ FHL2 has been reported to bind to ERK 1/2 in the cytosol and to inhibit activation and translocation to the nucleus when it is bound.¹⁷ One could hypothesize that part of the role of 7 integrin is to maintain ERK 1/2 in the cytosol and inhibit its translocation to the nucleus. Alternatively, 7 integrin may play a role in modulating the signaling cascade that leads to activation of ERK 1/2.

In addition to potential direct modulation of ERK 1/2 activity by 7 integrin, the effect of 7 integrin on ERK 1/2 activation in SMCs may be indirectly mediated through increased expression of integrins that activate ERK1/2. Specifically, vß3 and 5ß1 integrins are increased in various pathologies including hypertension, atherosclerosis, and restenosis.⁴ Ligation of these integrins induces ERK activity, which may account indirectly for the increased activation of ERK 1/2 in 7 integrin–null SMCs. Thus, the studies initiated by Welser et al may lead to some key mechanistic insights into how interaction with ECM proteins mediates SMC growth and differentiation. The importance of 7 integrin in vascular remodeling and in the response to injury is illustrated in this study by the profound increase in vascular remodeling, neointimal formation, and loss of vascular compliance in the carotid arteries of 7 integrin–null mice subjected to ligation.

In summary, Welser et al³ report a role for 7 integrin in modulating SMC proliferation in vitro and in modulating the arterial response to injury in vivo. The authors demonstrate that one of the mechanisms by which 7 integrin may influence these pathways is by inhibiting the activation and nuclear translocation of ERK 1/2, a pathway that is known to play a crucial role in modulating proliferation and phenotypic status of smooth muscle cells. The potential sites of modulation of the ERK1/2 pathway by 7 integrin engagement are illustrated in the Figure.

	Acknowledgments

 
Sources of Funding

This work was supported by grants to E.W. from the Muscular Dystrophy Association (MDA3681), American Heart Association-Texas Affiliate (0555116Y), and NIH (R21 EB004106).

Disclosures

None.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top References

 

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Related Article:

Loss of the 7 Integrin Promotes Extracellular Signal-Regulated Kinase Activation and Altered Vascular Remodeling

Jennifer V. Welser, Naomi Lange, Cherie A. Singer, Margaret Elorza, Paul Scowen, Kathleen D. Keef, William T. Gerthoffer, and Dean J. Burkin
Circ. Res. 2007 101: 672-681. [Abstract] [Full Text] [PDF]

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