Journal of Vascular Surgery
Volume 45, Issue 6, Supplement , Pages A15-A24, June 2007

Smooth muscle cell signal transduction: Implications of vascular biology for vascular surgeons

  • Akihito Muto, MD, PhD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • ,
  • Tamara N. Fitzgerald, MD, PhD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • ,
  • Jose M. Pimiento, MD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • Saint Mary’s Hospital, Waterbury, Conn
    • ,
  • Stephen P. Maloney, MD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • Saint Mary’s Hospital, Waterbury, Conn
    • ,
  • Desarom Teso, MD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Saint Mary’s Hospital, Waterbury, Conn
    • ,
  • Jacek J. Paszkowiak, MD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Saint Mary’s Hospital, Waterbury, Conn
    • ,
  • Tormod S. Westvik, MD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • ,
  • Fabio A. Kudo, MD, PhD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • ,
  • Toshiya Nishibe, MD, PhD

      Affiliations

    • Fujita Health University, Toyoake, Aichi, Japan
    • ,
  • Alan Dardik, MD, PhD

      Affiliations

    • Departments of Surgery, Yale University School of Medicine, New Haven, Conn
    • Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Conn
    • VA Connecticut Healthcare System, West Haven, Conn
    • Corresponding Author InformationReprint requests: Alan Dardik, MD, PhD, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave, Room 436, New Haven, CT 06519.

Received 18 January 2007; accepted 17 February 2007.

Article Outline

Vascular smooth muscle cells exhibit varied responses after vessel injury and surgical interventions, including phenotypic switching, migration, proliferation, protein synthesis, and apoptosis. Although the source of the smooth muscle cells that accumulate in the vascular wall is controversial, possibly reflecting migration from the adventitia, from the circulating blood, or in situ differentiation, the intracellular signal transduction pathways that control these processes are being defined. Some of these pathways include the Ras-mitogen–activated protein kinase, phosphatidylinositol 3-kinase-Akt, Rho, death receptor-caspase, and nitric oxide pathways. Signal transduction pathways provide amplification, redundancy, and control points within the cell and culminate in biologic responses. We review some of the signaling pathways activated within smooth muscle cells that contribute to smooth muscle cell heterogeneity and development of pathology such as restenosis and neointimal hyperplasia.

 

Under normal homeostatic conditions found in healthy vascular physiology, vascular smooth muscle cells (SMCs) ordinarily have a low turnover rate, with low baseline levels of both proliferation and apoptosis.1, 2 Acceleration of the rate of SMC turnover, with increases in the rates of both proliferation and apoptosis, is thought to be involved in the pathogenesis of atherosclerotic lesions, restenosis after interventional therapy, and vein graft arterialization.1, 2, 3, 4, 5, 6 For example, one theory suggests that the combined action of growth factors, proteolytic agents, and extracellular matrix proteins that are produced by a dysfunctional endothelium or inflammatory cells, or both, induce migration of resident SMCs from the media into the neointima and subsequent neointimal SMC proliferation to form atherosclerotic lesions.3, 7, 8

SMCs demonstrate a heterogeneous population of cells even in normal vascular tissue, however. Spindle-shaped differentiated SMCs show contractile properties, with a low frequency of proliferation, and are induced into this phenotype by heparin and transforming growth factor-β (TGF-β). Rhomboid-shape dedifferentiated SMCs show a high degree of protein synthesis, proliferation, and migratory activity, and are induced into this phenotype by basic fibroblast growth factor (bFGF) and platelet-derived growth factor-BB (PDGF-BB).7

The source of these different SMC phenotypes is controversial and has been studied most extensively after vascular interventions. Some of the potential sources of heterogeneous SMC populations that contribute to vascular remodeling include migration of cells from the adventitia, in situ differentiation and expansion, or accumulation from distant sources such as the bone marrow.

The myofibroblast SMC phenotype is thought to be a marker of SMCs that are involved in and accumulate during pathologic interactions such as restenosis, with increased expression of several markers of SMC differentiation, as well as increased proliferation, migration, and production of extracellular matrix proteins, cytokines, and chemokines.8, 9, 10, 11 Several groups have reported that myofibroblasts are derived from the adventitia and are involved in neointimal formation as well as vein graft arterialization.8, 12, 13, 14, 15, 16

In addition to the potential adventitial source of myofibroblasts that may contribute to SMC remodeling, bone marrow-derived progenitor cells (BMD PC) (stem cells) may also contribute to the heterogeneity of cells involved in vascular wall remodeling. BMD PCs are known to be released into the circulation after mechanical, immunologic, or humoral stimulation after vascular injury.17, 18 Although the mechanisms by which SMCs participate in formation of atherosclerotic lesions are becoming established, similar mechanisms of progenitor cell activation during homing and contribution to restenosis may also be active in SMCs after vascular interventions or during vein graft arterialization.19, 20

Most vascular structures develop from the mesoderm, but SMCs develop from several embryologically distinct origins; for example, SMCs in the branchial arch-derived vessels derive from the neural crest, and coronary artery SMCs derive from the overlying endothelium.7, 21 Recent studies also suggest that BMD PCs have the ability to develop into SMCs with the typical phenotype of neointimal SMCs, hypercholesterolemia-induced neointimal cells, and SMCs associated with transplant arteriopathy.1, 22, 23, 24, 25

During SMC development, the myogenic process requires expression of SMC-specific genes such as vimentin, α-actin, SM-22, caldesmon, calponin, SM-myosin heavy chain, and smoothelin.7, 8, 26, 27 These SMC-specific genes are characterized by their stimulated expression upon activation of their promoter CArG box element by the transcriptional factor serum response factor (SRF), with the cofactor myocardin.26, 28, 29 Control of this process is thought to be mediated by phosphorylated Elk-1, which is activated by the extracellular signal-regulated kinase 1/2 (ERK1/2) or phosphatidylinositol 3-kinase (PI3K)-Akt pathways, or both, resulting in inhibition of SRF-myocardin activation of SMC gene expression.

Although the contractile differentiated SMC phenotype is the typical SMC phenotype that comprises the vascular wall under most normal physiologic conditions, and the synthetic dedifferentiated SMC phenotype exists during developmental or pathologic conditions, the molecular mechanisms involved in the regulation of SMC phenotype and in the ability of SMC to change phenotype are not well established.7, 30, 31 Some of the many factors that may influence SMC phenotype include mechanical forces, contact agonists, reactive oxygen species, endothelial-SMC interactions, thrombin, neuronal factors, TGF-β1, and extracellular matrix components such as laminin and type I and IV collagens.1, 19, 32, 33, 34, 35, 36, 37, 38, 39 As such, it is difficult to study the in vivo SMC contractile phenotype, because of phenotype switching rapidly upon SMC isolation and culture in vitro. This paradoxical but reversible phenotype switching is one of the interesting unique characteristics of SMCs.

The pathologic accumulation of different SMC populations is of crucial importance to vascular surgeons. After vascular wall injury, whether accumulating from disease pathophysiology or after surgical interventions, ligand molecules such as growth factors, inflammatory factors, and reactive oxygen and nitrogen species are induced in the vessel or graft wall. These upstream induction factors stimulate SMC intracellular signal transduction pathways, culminating in SMC gene expression that leads to the lesions of restenosis and neointimal hyperplasia. In this review, we focus on SMC signal transduction that contributes to their heterogeneity and development of pathology. These SMC intracellular signal transduction pathways may be attractive points of control to potentially limit vascular disease due to SMCs and prolong the value of surgical interventions.

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Smooth muscle cell pathophysiology and signal transduction 

Signal transduction pathways provide amplification, redundancy, and control points within the SMC and culminate in biologic responses. The discovery of the G-protein families led to the concept of signal transduction cascades, as we know the field today, but was preceded by years of discovery of how signals were transmitted by hormones, hormone receptors, and second messengers such as calcium and cyclic nucleotides that established the field of classical signal transduction. Although these signal cascades seem to be complex, biologic stimuli are often present in low concentration, and both extracellular signals and intracellular responses must be amplified to induce a cell response. Of importance is that the complexity of these pathways may serve to both integrate the signal, ensuring that the cell’s response—which may be significant and even induce cell death—is appropriate for that signal, and allow for signal propagation with fidelity in the face of damaged cell machinery, such as may occur during normal aging. Understanding these pathways may allow control, perhaps stimulating desirable responses and limiting undesirable ones.

Protein kinases play an important role in signal transduction 

One way to rapidly accomplish intracellular signal transduction is to add phosphate groups to other proteins. This process is known as phosphorylation and is accomplished by enzymes called kinases. In particular, two classes of kinases, the serine/threonine kinases and the tyrosine kinases, play critical roles in mammalian biology. In general, serine/threonine kinases have broad substrate specificity even though they bind to a limited number of amino acid sequences. These kinases include the well-known protein kinase A (PKA), protein kinase B (PKB; also known as Akt), protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and TGF-β superfamilies.

Conversely, because only 0.1% of tyrosine exists as a potential site of phosphorylation by kinases, tyrosine kinases also have critical regulatory and signaling roles. Tyrosine kinases exist in two different families. The first broad class of these kinases interacts with membrane-bound receptor tyrosine kinases such as PDGF receptor, epidermal growth factor (EGF) receptor, insulin-like growth factor-I (IGF-I) receptor, and the Scf1/c-kit receptor. The second class of tyrosine kinases is the nonreceptor type kinases that interact with downstream targets of receptor tyrosine kinases, and include c-Src, Jak, and Fak. Compared with serine/threonine kinases that are typically activated by cyclic adenosine monophosphate, cyclic guanosine monophosphate, Ca2+, calmodulin, and diacylglycerol, tyrosine kinases are activated by dimerization and autophosphorylation.

Further propagation of the receptor tyrosine kinases-transduced signal is by several pathways, including the Grb-Sos-Ras-MAPK, PI3K-Akt, phospholipase C γ-PKC/Ca2+, and janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. These signaling pathways culminate in modification of several cell behaviors such as protein synthesis, cell proliferation, cell survival, and migration, as well as gene transcription.

Signal transduction from receptor tyrosine kinases is controlled at several points, including negative feedback signals. Signals are also directly and selectively inhibited by protein tyrosine phosphatases, phospholipid dephosphorylases, such as phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and src-homology 2-containing inositol 5′ phosphatase (SHIP). The kinases are also deactivated by ubiquitination.

Regulation of smooth muscle cell phenotypic switching 

One of the most interesting features of SMCs is that they are not terminally differentiated in mature vascular tissue, allowing modulation of their phenotype under certain conditions. SMC dedifferentiation and phenotype change is thought to be an important aspect of vascular wall remodeling during atherosclerosis and neointimal hyperplasia. Differentiated SMCs have a spindle shape, low proliferation rate, and physiologic contractile functions. Dedifferentiated SMC have a rhomboid or epithelioid shape, high proliferation, and migration activity, increased proteolytic activity, lower levels of cytoskeletal and contractile proteins, and high sensitivity to apoptotic stimuli.7, 26

Despite the well known and important role that SMC dedifferentiation and phenotype switching plays in repair of vascular wall injury, very few factors and pathways have been identified that modulate these phenotypic changes (Fig 1).26, 40 PDGF-BB is one of the few factors implicated in SMC phenotype switching. It is the only factor yet described that can induce a profound suppression of the SMC marker genes SM α-actin, SM-myosin heavy chain, and SM22α.26, 40, 41, 42, 43, 44, 45, 46

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  • Fig 1. 

    Signaling during smooth muscle cell (SMC) phenotype switching. The left side of the figure denotes pathways involved in signaling during SMC differentiation to the contractile phenotype. Insulin growth factor-I (IGF-1) causes expression of genes associated with the contractile, differentiated phenotype through the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, while at the same time blocks the Ras-mitogen-activated protein kinase (MAPK) pathway with the insulin receptor substrate-I (IRS-I)/Scr homology protein 2 (SHP2) complex. The right side of the figure denotes pathways involved in signaling during SMC phenotype switching to the synthetic phenotype. Several growth factors stimulate SMC phenotype switching by stimulating MAPK directly as well as by cleaving the IRS-I/SHP2 complex. MAPK transposition to the nucleus inhibits transcription of genes associated with the contractile phenotype and stimulates expression of genes associated with growth. Signals from each cascade inhibit the opposite cascade. PDGF, Platelet derived growth factor; EGF, epidermal growth factor; FGF, fibroblast growth factor 2; p, phosphorylation.

Kawai and Owens40 recently reviewed several pathways that may be involved in SMC phenotype modulation. Some of these pathways include Krüppel-like factor 4, phosphorylated Elk-1, HERP1, FOXO4, YY1, FHL2, and several homeobox proteins. For example, Krüppel-like factor 4 is induced by PDGF-BB and potently represses the expression of multiple differentiated SMC marker genes through a combination of effects, including suppression of myocardin expression, inhibition of SRF binding to intact chromatin, and suppression of myocardin-induced gene activation.10, 47, 48

Another transcriptional factor, Elk-1 (a ternary complex of Ets domain proteins), can induce PDGF-BB and suppress SMC marker genes including SM22α and SM α-actin. This is accomplished through suppression of CArG promoter element-SRF-myocardin dependent transcription.28, 41 Elk-1 is phosphorylated by PDGF-BB and signals downstream though MAPK/ERK kinase 1/2 (MEK1/2) -ERK1/2, ultimately cleaving SRF-myocardin.

IGF-I maintains the differentiated SMC phenotype by triggering the PI3K and PKB/Akt pathways. This cascade also blocks dedifferentiation depending on the recruitment of src homology protein 2 (SHP2) by insulin receptor substrate-1 (IRS-I).49, 50 SHP2/IRS-I cleavage is induced by PDGF, FGF, or EGF, and results in activation of the MEK-ERK1/2 and MAPK kinase 6 (MKK6)-p38MAPK pathways, mediated by the intermediate Grb2/Sos complex and Ras activation (Fig 1). Transcriptional and splicing factors then induce cell migration, proliferation, and extracellular matrix synthesis.49, 50 Some evidence exists that that IGF-I may not maintain SMC differentiation,51, 52, 53, 54, 55 but it is likely that IGF-I secretion plays an important role in SMC differentiation, proliferation, and migration.

Regulation of smooth muscle cell proliferation and migration 

After switching phenotype, SMCs migrate and proliferate in the vascular wall to promote healing of vessel injury. Proliferation and migration of dedifferentiated SMCs results in accumulation of cells and formation of the lesions of atherosclerosis, restenosis, or neointimal hyperplasia. This phenomenon is thought to be stimulated by growth factors within the injured vascular wall that regulate downstream signal transduction in SMCs, such as PDGF-BB and bFGF (Fig 2). These factors stimulate SMC pathways such as the Ras-MAPK and PI3K-Akt pathways that stimulate cell proliferation, and the Rho kinase family monomer G proteins Cdc42, Rac, and Rho that stimulate cell migration. These pathways promote phenotype switching, migration, and proliferation and also regulate extracellular matrix synthesis.56

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  • Fig 2. 

    Proliferative signaling during smooth muscle cell (SMC) response to injury. The figure shows convergent signaling pathways resulting in protein synthesis and cell proliferation, leading to restenosis and neointimal hyperplasia. Implications of vascular intervention may include inducing growth factors that are SMC mitogens and chemoattractants. These factors stimulate SMC signal transduction pathways including the Ras-mitogen-activated protein kinase (MAPK) and the PI3K-Akt-mammalian target of rapamycin (mTOR) pathways for growth gene transcription. PDGF-BB, Platelet-derived growth factor-BB; bFGF, basic fibroblast growth factor; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol bisphosphate; Grb2, growth factor receptor-bound protein 2; PI3K, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent kinase 1; MEK, MAPK/ERK kinase 1/2; Sos, son of sevenless.

The cellular source of these factors that stimulate SMCs is not clear, as vascular wall injury can induce humoral, autocrine, and paracrine growth factors such as PDGF-BB, bFGF, and HB-EGF from endothelial cells, SMCs, and invasive cells such as macrophages and platelets.6, 57, 58, 59, 60, 61 We have previously shown that nonlaminar shear stress, such as might be present after vessel injury, results in ERK1/2 activation from both PDGF-BB and interleukin-1α and results in SMC chemotaxis and proliferation.62, 63

The MAPK/ERK cascade is one of the well-known signal transduction pathways for SMC proliferation and induction of additional growth factor secretion.64, 65, 66, 67, 68 A protein-tyrosine kinase (PTK) receptor is activated by a growth factor, resulting in receptor phosphorylation and binding of adaptor proteins such as Grb2 and Shc to the activated receptor. Adaptor protein binding leads to Ras activation of the GTP-binding protein family, by the mammalian son-of-sevenless (mSOS; guanine nucleotide exchange factor), activating Raf MAPKK/MEK and the downstream molecules, p44 MAPK/p42 MAPK (ERK1/2). Phosphorylated MAPK enters the nucleus to form a complex with the transcriptional factors Elk-1 and Sap1 (an Ets family member), inducing transcription by binding to the SRE promoter of genes such as c-fos. This mechanism is thought to be critical in the regulation of gene expression for proliferation, migration, differentiation, and phenotypic switching (Fig 2).58, 69, 70, 71, 72, 73, 74, 75

It is typical for many stimuli to activate multiple signal transduction cascades. For example, PTK receptors also activate the PI3K-Akt pathway, in addition to the MAPK pathway, when stimulated by signals that induce cell proliferation and cell survival. The phosphorylated PTK receptor activates PI3K, phosphorylating PI(3,4)P2 to form PI(3,4,5)P3. The PH domain of Akt recruits PI(3,4,5)P3 on the cell membrane, and 3-phosphatidylinositol-dependent kinase (PDK) 1/2 then phosphorylate Akt on either Thr308 or Ser473. Phosphorylated Akt activates the mammalian target of rapamycin (mTOR)-raptor complex to trigger cell growth, cell survival, nitric oxide production, cell proliferation and cell cycling, and delaying G1/S exit.76, 77, 78, 79, 80, 81, 82, 83 Of interest is that these pathways all interact with each other. For example, activated PKA can have negative crosstalk with the Ras-MAPK and PI3K-Akt pathways as well as promote cell proliferation at the genetic level.64 Negative control of these pathways is also by phosphatases such as PTEN, which controls Akt pathway activation by inhibition of PI(3,4,5)P3 phosphorylation and inhibition of PI3K activity.84

The Rho small GTP-binding protein family induces SMC migration by control of the intracellular cytoskeletal architecture. The G-protein-coupled receptor can be activated by angiotensin II, thrombin, endothelin-1, or Ras that is recruited by activated PTK receptors and can induce Rho family (Rho, Rac, Cdc42) activation. This event stimulates Rho kinase or mDia, and reconstruction of the actin filament or F actin, resulting in cell migration.85, 86 Activated Rho also induces MEK1/MLKs/MEK4 activation, upstream of c-Jun N-terminal kinase (JNK), and induces cell differentiation, survival, and apoptosis. There is evidence of Rho activation in vascular injury and transplantation, and that this pathway induces cell mitogenesis, actin polymerization, cell migration, and neointimal formation.87, 88, 89, 90, 91, 92, 93

Regulation of extracellular matrix accumulation 

During SMC migration, successful production and remodeling of the extracellular matrix is necessary to form the neointima.94 Of interest is that the converse is also true; that is, degradation of the extracellular matrix during vascular injury induces SMC migration and proliferation. PDGF, angiotensin-II, and TGF-β have the ability to control extracellular matrix stability by changing the extracellular matrix components synthesized and secreted by SMCs.95, 96, 97 bFGF decreases SMC elastin production through ERK1/2 pathway activation.98 Elastin is abundant in the normal media, but a decrease in aortic elastin can induce plaque fragility in atherosclerosis and be associated with vessel weakening such as occurs during aneurysm formation.99

Extracellular matrix remodeling is the net result of the balance of matrix production and degradation; extracellular matrix synthesis is generally regulated by the matrix metalloproteinases (MMP), whereas extracellular matrix degradation is regulated by MMP inhibitors such as tissue inhibitor of metalloproteinase (TIMP) and reversion-inducing-cysteine-rich protein with Kazal motif (RECK). In vascular remodeling, MMPs not only synthesize matrix but also induce extracellular matrix degradation and remodeling in addition to stimulating cell proliferation and migration.40, 100 The interactions between the MMP-TIMP/RECK systems are not well described and are the subject of active investigation.

Induction of the SMC dedifferentiated phenotype during extracellular matrix degradation is strongly related to cell-to-matrix and cell-to-cell adhesion molecules. Growth factors interact with these adhesion molecules to induce SMC migration and proliferation.101 For example, nectin is not only found in cell-to-cell junctions but can also activate Cdc42 and Rac, a small GTP-binding protein with PTK receptor-activating properties.102, 103, 104 Cadherin can also activate Rac. Cdc42 and Rac can then each modulate reorganization of the actin cytoskeleton and activate additional signal transduction cascades such as JNK.105

Bone marrow–derived progenitor cell differentiation 

It has been recently described that BMD PCs may play an important role in vascular wall remodeling. Mouse embryonic stem cells can develop a SMC phenotype when activated by TGF-β1 through Smad-2/3.47 Pluripotent 10T1/2 cells demonstrate modulation of this response by bFGF-induced MEK signaling and suppression of SRF transcription.40 PDGF-BB induces TR-BME2 cells, a murine BMD endothelial progenitor cell (EPC) line, to differentiate into contractile-type and synthetic-type SMCs.97

Extracellular matrix and adhesion molecules have been reported to participate in the differentiation of BMD EPCs into SMCs. Smooth muscle progenitor cells have been found to display large numbers of α1β1 and α5β1 integrins, more than endothelial cells, which can capture fibronectin. This observation leads to the hypothesis that specific integrin expression in progenitor cells may provide key signaling in cell development.19, 106, 107 The exciting discovery of these BMD stem cells offers vascular surgeons the possibility to improve postinterventional vascular or vein graft patency and also may provide for the creation of novel conduits in vascular surgery such as tissue-engineered vascular autografts.108, 109 However, the details of downstream signaling pathways are not yet well defined despite mounting evidence of a role for stem cells in the response to vascular injury.

Regulation of smooth muscle cell apoptosis 

Apoptosis is widely known as programmed cell death that is a part of normal development, senescence, and other diverse biologic processes. Accumulation of normal and abnormal tissue depends on the delicate balance between cell proliferation and apoptosis; as such, it is difficult to assess the importance of apoptosis without careful measurements of both proliferative and apoptotic components. Neointimal hyperplasia and restenosis after vascular interventions also involve the SMC apoptotic pathway during vascular wall remodeling. In the rat carotid artery balloon injury model, approximately 70% of medial SMCs showed evidence of apoptosis only 1 hour after injury. Despite this early decrease in SMC numbers, neointima formation continues for several weeks.110 Another biologic stimulant of SMC apoptosis is laminar shear stress, suppressing SMC proliferation and restenosis after an endothelial-denuding injury such as angioplasty (Fig 3).111

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  • Fig 3. 

    Apoptotic signaling during smooth muscle cell (SMC) response to injury. The figure shows divergent pathways resulting in control of apoptosis, leading to different outcomes. The extrinsic apoptosis pathway is stimulated by signals external to the SMC, whereas the intrinsic apoptosis pathway is stimulated by signals internal to the SMC nucleus or mitochondria, or both. In the extrinsic pathway, apoptosis ligands activate caspase-8 and caspase-10 or c-Jun N-terminal kinase (JNK). The intrinsic pathway is activated by DNA damage or genetic programs and induces the apoptosis activating factor 1 (Apaf1)-caspase-9 complex directly or through the release of cytochrome c. Both the internal and external pathways activate caspase-3, caspase-5, and caspase-7 to effect apoptosis. TNFα, Tumor necrosis factor-α; PKA, protein kinase A; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; Cyto c, cytochrome c; UV, ultraviolet radiation.

Known triggers of vascular cell apoptosis include oxidized low-density lipoprotein, oxysteroles, reactive oxygen or nitrogen species, radiation, cytokines, and viral and bacterial products.100 Suppressors of apoptosis include turbulent shear stress, low levels of nitric oxide, growth factors, the inhibitor of apoptosis protein family, vitamins C and E, and other antioxidants. Several apoptotic ligands such as interferon-γ, FasL, TNFα, interleukin 1, reactive oxygen or nitrogen species, and radiation can indirectly induce SMC apoptosis via activated T-cell antigen presentation, proinflammatory mediators, or activated macrophage immune priming or phagocytosis.

Signal transduction to transmit the apoptotic death signal is carefully regulated. There are two well-defined upstream pathways, the extrinsic and the intrinsic pathways (Fig 3). In the extrinsic pathway, ligands activate the apoptotic pathways through receptors such as Fas, TNF receptor, and the DR3/4/5 receptors, leading to downstream caspase activation and mitochondrial dysfunction. Fas activation due to FasL expression on T cells, macrophages, and monocytes induces polymerization of the Fas-associated death domain and activation of pro-caspase-8. Caspase-8 cleaves a member of the Bcl-2 family, Bid, inducing cytochrome c release from the mitochondria, and activating caspase-9; apoptosis is accomplished by caspase-3 activation.112, 113 The TNF receptor similarly stimulates apoptosis by activation of the caspase-8 pathway and also simultaneously activates the regulatory nuclear factor-κB pathway, protecting the cell from apoptosis.114, 115

The Bcl-2 protein family also regulates the apoptosis pathways to influence cell survival; this family forms heterodimers between apoptosis-inhibiting proteins such as Bcl-2, Bcl-XL, and A1, and inducing proteins such as Bax, Bad, and Bid, regulating cell survival.116 Cell survival factors inhibit Bad activity by several pathways, including by PKA, ERK1/2, PKC, and PI3K-Akt pathway activation (Fig 3).

In contrast, the intrinsic apoptotic pathway is directly stimulated by gene transcription, DNA damage, mitochondrial stress, and endoplasmic reticulum stress. These stimuli directly activate caspase-1, caspase-2, and caspase-9, or indirectly by p53 or cytochrome c (Fig 3). These cascades induce Apaf1 polymerization to activate caspase-9. Finally, as with the extrinsic pathway, caspase-3 is activated by caspase-9-Apaf1 to induce apoptosis.

Signal transduction in vascular pathology 

Diabetes mellitus is one of the major risk factors for vascular disease.117, 118 Diabetic patients with hyperglycemia often have accelerated neointimal formation, and this correlates with increased PDGF-β receptor and TGF-β receptor expression by SMCs.119, 120, 121 Downstream of the PTK receptors, hyperglycemia induces p38 MAPK—but not ERK1/2—and activates both PKC-dependent and PKC-independent pathways in rat aortic SMCs.122

Evidence also exists that IGF-binding protein is degraded in hyperglycemic conditions, inducing IGF-I levels that stimulate the differentiated SMC phenotype.123 Because IGF-I is also associated with inhibition of the synthetic SMC phenotype, and SMC proliferation and migration (Fig 1), IGF-I may also have potential as an antiproliferative therapeutic agent. Other proteins in this pathway may also have potential as therapeutic agents; for example, pregnancy-associated plasma protein-A, one of the metalloproteinases associated with IGF binding protein-4, significantly decreases neointimal formation.124

Conversely, the complexity of the signal transduction pathways precludes easy translation of in vitro and animal studies to the treatment of human patients. For example, diabetic patients may also induce extracellular matrix/cytoskeletal production through G-protein-coupled receptors; if so, then this additional mechanism of signaling produces IP3 and Ca2+ release as well.125

Restenosis after vascular interventions is associated with activation of SMC signal transduction pathways; accumulation of SMCs in restenotic lesions may be a source of symptoms.126 Identification of these SMC signal transduction pathways has led to identification of potential points of control. For example, rapamycin is an established inhibitor of vascular remodeling with use in drug-eluting stents in both the coronary and periphery beds.127, 128 Rapamycin inhibits neointimal formation after carotid artery balloon angioplasty in animal models and may be useful in human patients with advanced disease; for example, rapamycin inhibited neointima formation even in conditions of low flow, such as present in patients with extensive runoff disease (Fig 4). Of interest is that rapamycin does not affect low flow–induced inward remodeling (Fig 4), suggesting that its effects on signal transduction pathways and inhibition of neointimal hyperplasia are specific.

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  • Fig 4. 

    Relevance of the mammalian target of rapamycin (mTOR) signal transduction pathway in the response to vascular injury. The right carotid artery of New Zealand White rabbits was subjected to sham operation (control), balloon injury (B), outflow branch ligation to reduce flow (LF), or both balloon injury and reduction in flow (B+LF), and harvested after 21 days. Either rapamycin (5 mg/kg) or saline was orally administered daily from 48 hours before the procedure until harvest. In animals given rapamycin, serum levels (day 7) were therapeutic (mean, 10.9 ± 0.5 ng/mL; therapeutic range, 4 to 12 ng/mL; n = 21). Animals treated with rapamycin demonstrated significant inhibition of neointimal thickening in balloon-injured arteries (B), including arteries treated with low flow (B+LF; P < .0001). Negative remodeling was evident in all vessels in both low flow groups (LF, B+LF), and rapamycin did not affect this reduction in vessel size due to low flow. A, Low-power magnification. B, High-power magnification. Reprinted from Paszkowiak JJ, Maloney SP, Kudo FA, et al. Evidence supporting changes in Nogo-B levels as a marker of neointimal expansion but not adaptive arterial remodeling. Vasc Pharmacol 2007;46:293-301. Copyright 2007, with permission from Elsevier.

The intracellular target of rapamycin is the mTOR protein, which is normally phosphorylated by Akt (Fig 2). Rapamycin inhibits mTOR downstream activation, including JNK activation, and induces apoptosis.129 The two important mTOR downstream pathways are stimulation of S6K1/2 and suppression of 4E-BP1. c-Jun phosphorylation is required for activating 4E-BP1, but not S6K1/2, and takes place in a relative deficiency of p53, suggesting a role for rapamycin not only in molecular targeting for cancer but also in targeting immature SMCs as might be found in vascular injury. Accordingly, rapamycin inhibits SMC migration.130

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Conclusion 

SMCs are complex cells capable of existing in heterogeneous populations and switching phenotypes upon various stimuli. The signal transduction pathways controlling SMC activation and phenotype switching are becoming established and may suggest additional points of control. Additional pathways are present as well. For example, caveolin-1 signaling has been implicated in SMC proliferation and migration through a Ca2+ mediated pathway.131 Nitric oxide is implicated in SMC vasorelaxation through cytosolic soluble guanylate cyclase signaling. Nitric oxide signaling is also linked to the Akt pathway, and thus involved in cell migration, proliferation, and apoptosis. Intraluminal endothelial nitric oxide synthase gene delivery may reduce the response to vascular injury and may be another application of modulation of signal transduction pathways.132

The SMC signal transduction pathway control points are gradually appearing in new therapeutic modalities such as drug-eluting stents and local gene transduction.127, 128, 133, 134 As mechanisms of SMC signal transduction continue to be elucidated and understood, it is hoped that we will be able to provide improved care and quality of life for our patients.

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We especially thank Yukiko Muto for her extensive supporting contributions. This work is dedicated to the memory of Leonard J Perloff, MD, a mentor and inspiration to surgeon–scientists.

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 Competition of interest: none.This material is the result of work partially supported by National Institutes of Health awards 1 K08 HL079927 (A. D.) and 1 F32 HL086086 (T. N. F.), the American Vascular Association William J. von Liebig Award, as well as with resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, Connecticut.

PII: S0741-5214(07)00353-9

doi:10.1016/j.jvs.2007.02.061

Journal of Vascular Surgery
Volume 45, Issue 6, Supplement , Pages A15-A24, June 2007

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