Phenotypic modulation of arterial smooth muscle cells is associated with prolonged activation of ERK1/2

Roy, Joy; Kazi, Monsur; Hedin, Ulf; Thyberg, Johan

doi:10.1046/j.1432-0436.2001.067001050.x

Cited by 34 publications

(30 citation statements)

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“…Acute activation of ERK (30 min) by PDGF underlies the down-regulation of contractile proteins, including a-SMA and sm-MHC (Wang et al, 2004). Long-term activation of ERK is critical for mitogenic signals (Orsini et al, 1999;Roy et al, 2001;Kiermayer et al, 2005), which probably requires prolonged stimulation of the transcription machinery, whereas non-mitogenic stimuli provide only a transient activation of ERK (Kelleher et al, 1995;Roscioni et al, 2009). In the present study, PDGF induced a strong and sustained phosphorylation of ERK.…”

Section: Figuresupporting

confidence: 47%

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

Roscioni

Dekkers

Prins

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSE Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet‐derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo‐contractile phenotype, a process requiring activation of extracellular signal‐regulated kinase (ERK) and p70S6 Kinase (p70S6K). The effects of cAMP‐elevating agents on these processes is unknown. Here, we investigated the effects of cAMP elevation by prostaglandin E2 (PGE2) and the activation of the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (Epac) on PDGF‐induced phenotype switching in bovine tracheal smooth muscle (BTSM).EXPERIMENTAL APPROACH Effects of long‐term treatment with the PGE2 analogue 16,16‐dimethyl‐PGE2, the selective Epac activator, 8‐pCPT‐2′‐O‐Me‐cAMP and the selective PKA activator, 6‐Bnz‐cAMP were assessed on the induction of a hypo‐contractile, proliferative BTSM phenotype and on activation of ERK and p70S6K, both induced by PDGF.KEY RESULTS Treatment with 16,16‐dimethyl‐PGE2 inhibited PDGF‐induced proliferation of BTSM cells and maintained BTSM strip contractility and contractile protein expression in the presence of PDGF. Activation of both Epac and PKA similarly prevented PDGF‐induced phenotype switching and PDGF‐induced activation of ERK. Interestingly, only PKA activation resulted in inhibition of PDGF‐induced phosphorylation of p70S6K.CONCLUSIONS AND IMPLICATIONS Our data indicate for the first time that both Epac and PKA regulated switching of ASM phenotype via differential inhibition of ERK and p70S6K pathways. These findings suggest that cAMP elevation may be beneficial in the treatment of long‐term changes in airway disease.

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Section: Figuresupporting

confidence: 47%

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

Roscioni

Dekkers

Prins

et al. 2010

British J Pharmacology

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“…On the molecular level, phenotypic modulation of VSM cells depends on the activation of mitogen-activated protein (MAP) kinases (8). The epidermal growth factor (EGF) receptor is transactivated after G protein-coupled receptor (GPCR) activation and recruits the guanine nucleotide exchange factor (Sos) through adaptor proteins, Shc and Grb2, thereby initiating the canonical Ras/Raf/MEK/ERK cascade (9 -10).…”

mentioning

confidence: 99%

Requirement of an Intermediate Gene Expression for Biphasic ERK1/2 Activation in Thrombin-stimulated Vascular Smooth Muscle Cells

Sastre

Großmann

Reusch

et al. 2008

Journal of Biological Chemistry

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The expression of contractile proteins in vascular smooth muscle cells is controlled by still poorly defined mechanisms. A thrombin-inducible expression of smooth muscle-specific ␣-actin and myosin heavy chain requires transactivation of the epidermal growth factor (EGF) receptor and a biphasic activation of ERK1/2. Here we demonstrate that the sustained second phase of ERK1/2 phosphorylation requires de novo RNA and protein synthesis. Depolymerization of the actin cytoskeleton by cytochalasin D or disruption of transit between the endoplasmic reticulum and the Golgi apparatus by brefeldin A prevented the second phase of ERK1/2 phosphorylation. We thus conclude that synthesis and trafficking of a plasma membrane-resident protein may be critical intermediates. The principal function of vascular smooth muscle (VSM) 2 cells in a developed vascular system is the regulation of blood pressure and flow. In certain diseased states, however, VSM cells can undergo a phenotypic modulation toward a proliferative and secretory phenotype or by reverting toward the nonproliferative contractile phenotype (1). The transition from a differentiated phenotype to a fibroblast-like proliferative state is observed during the onset or progression of atherosclerosis (2-3), one of the most common diseases in developed countries (4 -5). Under these conditions, the VSM cell phenotype is reminiscent of that observed during vascular development, where VSM cells play a key role in morphogenesis of the blood vessel and exhibit a high proliferative index, migrate, and produce extracellular matrix components (6). Conditions that promote the proliferative phenotype include the combined action of growth factors, proteolytic enzymes, and exposure to extracellular matrix proteins (7).The reciprocal process has been observed upon completion of wound healing or during formation and organization of a fibrous cap. Under these conditions, VSM cells are exposed to various stimuli, including macrophage-and lymphocyte-derived cytokines and serum components that are currently being discussed as critical regulators of plaque stability.On the molecular level, phenotypic modulation of VSM cells depends on the activation of mitogen-activated protein (MAP) kinases (8). The epidermal growth factor (EGF) receptor is transactivated after G protein-coupled receptor (GPCR) activation and recruits the guanine nucleotide exchange factor (Sos) through adaptor proteins, Shc and Grb2, thereby initiating the canonical Ras/Raf/MEK/ERK cascade (9 -10). Activated MAP kinases of the extracellular signal-regulated kinase (ERK1/2) family in turn translocate to the nucleus and phosphorylate nuclear transcription factors or transcriptional coactivators (11).Within the family of EGF receptor ligands, heparin-binding EGF (HB-EGF) has been implicated in vascular remodeling because it is a potent mitogen, acts as a chemotactic factor for VSM cells, and is abundantly expressed in vascular lesions such as atherosclerosis (12). Upon membrane insertion and signal peptide cleavage, pro-HB-E...

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“…PDGF-activated versican core protein expression is mediated via PKC but also via an ERK-dependent pathway. ERK activation has been associated with an ASMC proliferative and migratory phenotype (41)(42)(43). This study provides evidence that PKC and ERK are independent signaling pathways for the following reasons.…”

Section: Discussionmentioning

confidence: 65%

Platelet-derived Growth Factor Differentially Regulates the Expression and Post-translational Modification of Versican by Arterial Smooth Muscle Cells through Distinct Protein Kinase C and Extracellular Signal-regulated Kinase Pathways

Cardoso¹,

Little

Ballinger

et al. 2010

Journal of Biological Chemistry

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The synthesis of proteoglycans involves steps that regulate both protein and glycosaminoglycan (GAG) synthesis, but it is unclear whether these two pathways are regulated by the same or different signaling pathways. We therefore investigated signaling pathways involved in platelet-derived growth factor (PDGF)-mediated increases in versican core protein and GAG chain synthesis in arterial smooth muscle cells (ASMCs). PDGF treatment of ASMCs resulted in increased versican core protein synthesis and elongation of GAG chains attached to the versican core protein. The effects of PDGF on versican mRNA were blocked by inhibiting either protein kinase C (PKC) or the ERK pathways, whereas the GAG elongation effect of PDGF was blocked by PKC inhibition but not by ERK inhibition. Interestingly, blocking protein synthesis in the presence of cycloheximide abolished the PDGF effect, but not in the presence of xyloside, indicating that GAG synthesis that results from PKC activation is independent from de novo protein synthesis. PDGF also stimulated an increase in the chondroitin-6-sulfate to chondroitin-4-sulfate ratio of GAG chains on versican, and this effect was blocked by PKC inhibitors. These data show that PKC activation is sufficient to cause GAG chain elongation, but both PKC and ERK activation are required for versican mRNA core protein expression. These results indicate that different signaling pathways control different aspects of PDGF-stimulated versican biosynthesis by ASMCs. These data will be useful in designing strategies to interfere with the synthesis of this proteoglycan in various disease states.

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Phenotypic modulation of arterial smooth muscle cells is associated with prolonged activation of ERK1/2

Cited by 34 publications

References 50 publications

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

Requirement of an Intermediate Gene Expression for Biphasic ERK1/2 Activation in Thrombin-stimulated Vascular Smooth Muscle Cells

Platelet-derived Growth Factor Differentially Regulates the Expression and Post-translational Modification of Versican by Arterial Smooth Muscle Cells through Distinct Protein Kinase C and Extracellular Signal-regulated Kinase Pathways

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