Transient reexpression of an embryonic autonomous growth phenotype by adult carotid artery smooth muscle cells after vascular injury

Weiser‐Evans, Mary C.M.; Quinn, Bryan E.; Burkard, Michael; Stenmark, Kurt R.

doi:10.1002/(sici)1097-4652(200001)182:1<12::aid-jcp2>3.0.co;2-g

Cited by 25 publications

(34 citation statements)

References 49 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous work suggested serum-independent growth is actively controlled through the timed acquisition of a suppressor activity. 3 We therefore focused our studies on the potential role of PTEN, an endogenous negative regulator of PI3K signaling, in controlling embryonic and neointimal SMC serum-independent growth. PTEN, a dual-specificity lipid and protein phosphatase, promotes cell cycle arrest by downregulating PI3K/Akt signaling 9 -12 and is inactive when phosphorylated.…”

Section: Decreased Activity Of Pten Is Associated With High In Vivo Smentioning

confidence: 99%

“…1,2 However, after injury to an adult artery, transient increases in SMC replication to levels similar to those exhibited during embryonic life are observed in the neointima. 2,3 Corresponding to high in vivo growth rates, SMCs cultured from embryonic aortas exhibit a distinct growth phenotype characterized by rapid serum-stimulated growth and the ability to replicate in a mitogen-or serum-independent manner. 1 This growth phenotype is lost by fetal life, with fetal-, neonatal-, and adult-derived SMCs exhibiting slower growth rates in response to serum stimulation and loss of serum-independent growth.…”

mentioning

confidence: 99%

“…SMCs derived at specific times from injured adult vessels, however, exhibit a similar growth phenotype at a time correlating to peak in vivo neointimal SMC growth. 3 Thus, SMCs are capable of transiently reexpressing an embryonic-like, serum-independent growth phenotype. Additionally, we 3 reported adult-derived serumdependent SMCs possess a "suppressor activity" that continually and actively controls SMC replication by extinguishing serum-independent growth potential.…”

mentioning

confidence: 99%

“…3 Thus, SMCs are capable of transiently reexpressing an embryonic-like, serum-independent growth phenotype. Additionally, we 3 reported adult-derived serumdependent SMCs possess a "suppressor activity" that continually and actively controls SMC replication by extinguishing serum-independent growth potential. This suppressor activity is first detected in the fetal period of development when the potential for SMC serum-independent growth is no longer detected and is only lost or inactivated after vascular injury corresponding to reexpression of a serum-independent growth phenotype.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN

et al. 2004

Self Cite

View full text Add to dashboard Cite

Background-At distinct times during embryonic development and after vascular injury, smooth muscle cells (SMCs) exhibit a highly proliferative, serum-independent growth phenotype. The aim of the present study was to evaluate the functional role of S6 ribosomal protein (S6RP) and upstream positive and negative regulators in the control of SMC serum-independent growth. Methods and Results-We previously reported increased expression of S6RP mRNA was associated with this unique growth phenotype. Using immunohistochemistry and Western blot analysis, we report high levels of total and phospho-S6RP and increased levels of Akt and p70S6K phosphorylation, upstream positive regulators of S6RP, in rat embryonic aortas and adult balloon-injured carotid arteries compared with quiescent adult aortas and uninjured carotid arteries. Western blot analysis demonstrated that cultured embryonic and neointimal SMCs that exhibited serumindependent growth capabilities expressed high levels of S6RP and constitutively active Akt, mTOR, and p70S6K. Pharmacological and molecular inhibition of phosphatidylinositol 3-kinase (PI3K) signaling pathways, using PI3K inhibitors, rapamycin, or dominant-negative Akt adenovirus, suppressed embryonic and neointimal SMC serumindependent growth. Finally, decreased activity of PTEN, an endogenous negative regulator of PI3K signaling, was associated with high in vivo SMC growth rates, and morpholino-mediated loss of endogenous PTEN induced a serum-independent growth phenotype in cultured serum-dependent SMCs. Conclusions-The possibility exists that cells that exhibit a distinct embryonic-like growth phenotype different from traditional SMCs are major contributors to intimal thickening. Growth of SMCs that exhibit this phenotype is dependent on constitutive Akt and mTOR/p70S6K signaling and is actively inhibited through the timed acquisition of the endogenously produced growth suppressor PTEN. Key Words: cells Ⅲ restenosis Ⅲ muscle, smooth Ⅲ aorta Ⅲ carotid arteries V ascular smooth muscle cell (SMC) proliferation plays a prominent role in normal vessel development and in many vascular pathologies, including restenosis after angioplasty and stent placement and atherosclerosis. The mechanisms that regulate SMC proliferation during vascular development and in response to vascular injury in the adult blood vessel, however, have yet to be fully elucidated. During development, aortic SMCs undergo a phase of rapid proliferation, during which the vessel wall acquires its complement of SMCs. 1 Replication rates decrease as the animal matures, with SMCs eventually reaching a quiescent state in the adult animal. 1,2 However, after injury to an adult artery, transient increases in SMC replication to levels similar to those exhibited during embryonic life are observed in the neointima. 2,3 Corresponding to high in vivo growth rates, SMCs cultured from embryonic aortas exhibit a distinct growth phenotype characterized by rapid serum-stimulated growth and the ability to replicate in a mitogen-or serum-independent man...

show abstract

Section: Decreased Activity Of Pten Is Associated With High In Vivo Smentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, smooth muscle cells in intima express the genes that represent the characteristics of developmental stages of smooth muscle cells [36,37]. The changes of growth patterns and gene expression, the major events that cause neointima formation after vascular injury, are believed to be associated with the loss of intracellular growth control [38]. These data indicate that subcultured cells are the appropriate model to mimic the cells in both media and neointima in injured vessel wall.…”

Section: Cell Culturementioning

confidence: 99%

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

Chang¹

2011

J Diabet Metabol

View full text Add to dashboard Cite

Hyperinsulinemia, a major feature of type 2 diabetes and the metabolic syndrome, is believed to be highly associated with the occurrence of atherosclerosis and vascular restenosis [1][2][3]. In humans with insulin resistance, the frequency of restenosis after coronary angioplasty is significantly higher than those with normal insulinemia [4]. Animals with hyperinsulinemia show increased neointima formation caused by vascular injury via potentiating smooth muscle cell migration and proliferation [5][6][7]. The application of insulin sensitizers, such as synthetic thiazolidinediones (STD), significantly reduces carotid artery intima/ media thickness in patients with type 2 diabetes [8][9][10] and in animals with induced carotid injury [11][12][13][14]. However, the underlying mechanisms are not well understood. Recurrent stenosis after angioplasty is the result of increased smooth muscle cell proliferation in the media layer and migration to the intima in the wall of the vasculature. It is well established that vascular inflammation in response to angioplasty-induced injury is the initiator of increased neointima formation. Several experimental and clinical observations indicate that up regulation of pro-inflammatory cytokines in activated SMCs contributes to angioplasty-induced restenosis through promoting vascular smooth muscle cell migration and proliferation, a manifestation of an inflammatory wound healing process occurring in injured vessels [15][16][17]. Of the many cytokines involved in injury-induced inflammation, IL-6 is the major pro-inflammatory cytokine that contributes to vascular injuryinduced neointima thickening [18]. IL-6 is expressed and synthesized by a variety of cell types implicated in intimal hyperplasia. These include endothelial cells, macrophages, and smooth muscle cells. IL-6 induces a motogenic effect on vascular smooth muscle cells [19,20]. A significant correlation between the changes of IL-6 concentrations in the coronary circulation after PTCA and the degree of restenosis has been observed [21]. Monitoring variations in IL-6 has been proposed as an inflammatory marker to detect the early stage of cardiovascular diseases in order to develop a beneficial strategy to prevent the progression of the diseases. It was also reported that IL-6 induced the expression of acute phase proteins and several other cytokines and growth factors [22], suggesting that IL-6 may serve as a major initiator to trigger inflammation cascade responses that later lead to restenosis. One of the signal transduction pathways that mediates IL-6-mediated cellular responses is gp130/JAK/ STAT cascade [19]. The formation of IL-6 and the IL-6 receptor complex promotes the recruitment of gp130, followed by activation of Janus kinase (JAK). Activation of JAKs leads to tyrosine phosphorylation of gp130 and recruitment of STAT 3 . STAT 3 in turn becomes phosphorylated and dimerized, and translocate into the nucleus, where it binds to the target genes and regulates gene transcription and protein expression [19], leading t...

show abstract

Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn

Dakshinamurti

2005

Pediatric Pulmonology

121

View full text Add to dashboard Cite

Persistent pulmonary hypertension of the newborn (PPHN), among the most rapidly progressive and potentially fatal of vasculopathies, is a disorder of vascular transition from fetal to neonatal circulation, manifesting as hypoxemic respiratory failure. PPHN represents a common pathway of vascular injury activated by numerous perinatal stresses: hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury. As with other multifactorial diseases, a single inciting event may be augmented by multiple concurrent/subsequent phenomena that result in differing courses of disease progression. I review the various mechanisms of vascular injury involved in neonatal pulmonary hypertension: endothelial dysfunction, inflammation, hypoxia, and mechanical strain, in the context of downstream effects on pulmonary vascular endothelial-myocyte interactions and myocyte phenotypic plasticity.

show abstract

Transient reexpression of an embryonic autonomous growth phenotype by adult carotid artery smooth muscle cells after vascular injury

Cited by 25 publications

References 49 publications

Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN

Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn

Contact Info

Product

Resources

About