All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells

Axel, Dorothea I.

doi:10.1016/s0008-6363(00)00312-6

Cited by 96 publications

(77 citation statements)

References 34 publications

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“…We previously showed that atRA decreases the expression of smooth muscle ␣-actin in intimal SMCs. 9 In contrast, other investigators found that atRA increases the expression of both smooth muscle ␣-actin and smooth muscle myosin heavy chain 43,44 in SMCs from the medial layer of the vessel. This suggests that the differentiation state of the SMC influences the effects of atRA on the expression of contractile proteins.…”

Section: Discussionmentioning

confidence: 85%

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

Ocaya

Gidlöf²,

Olofsson³

et al. 2007

ATVB

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Objective-Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26 10 Retinoids inhibit intimal hyperplasia after vascular injury 6,9 by reducing SMC proliferation. 11 They are known to influence differentiation of various cell types, and previous studies indicate that retinoids can alter the phenotype of vascular SMCs. 9,12 To date, a number of genes have been identified as markers of intimal SMCs including tropomyosin 4, 13 cytokeratins, 14 and cellular retinol binding protein-1 (CRBP-1). 15 Interestingly, CRBP-1 is involved in retinoid metabolism, 16 suggesting an altered retinoid metabolism in the intima. Indeed, we previously demonstrated that intimal SMCs have higher capacity to metabolize retinol into the active metabolite, all-trans retinoic acid (atRA), than medial SMCs. 17 The inhibition of DNA synthesis in intimal SMCs, in contrast to increased DNA synthesis in medial SMCs on retinol stimulation, 17 further supports the concept of differential retinoid metabolism in these subsets of cells.The metabolism of retinoids is complex and involves multiple binding proteins and metabolizing enzymes. The synthesis of retinoic acid (RA) is a 2-step reaction involving substrate-specific enzymes and cellular retinol binding proteins. The first step is the reversible oxidation of retinol (ROH) into retinal by retinol dehydrogenases (RDH). 16,18 The second step, the oxidation of retinal into the biologically active RA, is carried out by retinal dehydrogenases (RalDH). RA activates 2 families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are ligand-inducible transcription factors. Retinoids exert their effects on gene transcription mainly through 2 active stereoisomers, atRA and 9-cis retinoic acid (9-cisRA). 19

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Section: Discussionmentioning

confidence: 85%

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

Ocaya

Gidlöf²,

Olofsson³

et al. 2007

ATVB

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“…ATRA typically inhibits 50-90% of aortic or pulmonary SMC proliferation induced by growth factors (8,10,11,13,23). We tested the hypothesis that ATRA may also inhibit the proliferation of airway SMCs.…”

Section: Effects Of Atra On Airway Smc Proliferation and Apoptosismentioning

confidence: 99%

“…ATRA inhibits PDGF-induced proliferation and induces apoptosis in rat and human aortic SMCs (11)(12)(13). In cultured pulmonary artery SMCs, ATRA inhibits serotonin-induced proliferation (8).…”

mentioning

confidence: 99%

Retinoic Acid Inhibits Airway Smooth Muscle Cell Migration

Day

Lee²,

Park³

et al. 2006

Am J Respir Cell Mol Biol

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Airway remodeling in chronic asthma is characterized by increased smooth muscle mass that is associated with the reduction of the bronchial lumen as well as airway hyperresponsiveness. The development of agents that inhibit smooth muscle growth is therefore of interest for therapy to prevent asthma-associated airway remodeling. All-trans retinoic acid (ATRA) suppresses growth of vascular smooth muscle cells (SMCs) from the systemic and pulmonary circulation. The present study investigated the effects of ATRA on human bronchial (airway) SMCs. Human bronchial SMCs were found to express mRNAs for retinoic acid receptor (RAR)-␣, -␤, -␥, and retinoid X receptor (RXR)-␣, -␤, but not RXR-␥. Although ATRA was not effective in inhibiting proliferation or in inducing apoptosis in airway SMCs, we found that ATRA (0.2-2 M) inhibited the SMC migration in response to platelet-derived growth factor (PDGF), as determined in a modified Boyden chamber assay. Both RAR and RXR agonists also blocked PDGF-induced airway SMC migration. ATRA also inhibited PDGF-induced actin reorganization associated with migration. PDGF-induced actin reorganization and migration were blocked by inhibitors of phosphatidylinositol 3 kinase (PI3K) and Akt. However, migration was blocked by inhibitors of the MEK/ ERK pathway, with no effect on cytoskeletal reorganization. ATRA suppressed PDGF-induced Akt activation without influencing ERK activation. RAR was found to form protein-protein interactions with the p85 PI3K subunit. These results suggest that retinoic acid inhibits airway SMC migration through the modulation of the PI3K/Akt pathway.

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“…Incubation of multipotential P19 embryonal carcinoma cells with retinoids induces differentiation of VSMCs through the induction of α-smooth muscle actin (28,29). Moreover, RA inhibits the production of several matrix metalloproteinases, and this inhibition may suppress the migration of VSMCs (30,31). Neointima formation after endothelial injury has also been shown to be inhibited by RA treatment in vivo (27,32,33).…”

Section: Discussionmentioning

confidence: 99%

Transcription Suppression of Thromboxane Receptor Gene Expression by Retinoids in Vascular Smooth Muscle Cells

et al. 2003

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All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells

Cited by 96 publications

References 34 publications

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

Retinoic Acid Inhibits Airway Smooth Muscle Cell Migration

Transcription Suppression of Thromboxane Receptor Gene Expression by Retinoids in Vascular Smooth Muscle Cells

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