Vascular Smooth Muscle Cell
            <i>Smad4</i>
            Gene Is Important for Mouse Vascular Development

Mao, Xia; DeBenedittis, Paige; Sun, Yong; Chen, Jianfeng; Yuan, Kaiyu; Jiao, Kai; Chen, Yabing

doi:10.1161/atvbaha.112.253872

Cited by 47 publications

(58 citation statements)

References 39 publications

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“…In addition, we determined the AKT/FOXO/Runx2 signaling axis in the atherogenic ApoE −/− mice, which developed atherosclerotic vascular calcification as we demonstrated previously 14, 36 . Consistently, HFD induced upregulation of Runx2 and vascular calcification (supplemental Figure IV).…”

Section: Resultsmentioning

confidence: 78%

“…The smooth muscle specific-PTEN deficient mice were generated by crossing PTEN exon 5 floxed mice (PTEN f/f ) 35 with the SM22α-Cre transgenic mice 14, 36 . Details of materials and experimental procedures are in the Methods section in the Online Data Supplement.…”

Section: Methodsmentioning

confidence: 99%

“…PTEN exon5 floxed mice (PTEN f/f ) mice 1 and SM22α-Cre transgenic mice 2, 3 were obtained from The Jackson Laboratory. The SM22α-Cre mice were bred with PTEN f/f to generate smooth muscle-specific PTEN deletion mice (PTEN Δ/Δ ).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of FOXO1/3 Promotes Vascular Calcification

Deng

Huang

Sun

et al. 2015

ATVB

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103

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Objective Vascular calcification is a characteristic feature of atherosclerosis, diabetes and end-stage renal disease. We have demonstrated that activation of AKT upregulates Runx2, a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of PTEN, a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO-mediated Runx2 upregulation and VSMC calcification. Approaches and Results SMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN deficient mice and atherogenic ApoE−/− mice, we further demonstrated AKT activation, FOXO phosphorylation and Runx2 ubiquitination in vascular calcification in vivo. Conclusions Our studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification, and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification.

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Section: Resultsmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of FOXO1/3 Promotes Vascular Calcification

Deng

Huang

Sun

et al. 2015

ATVB

Self Cite

103

View full text Add to dashboard Cite

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“…Differentiation of VSMCs is characterized by the appearance of SMC-specific contractile proteins (e.g., SMα-actin, SM22α, and SMemb), the expression of which is restricted to the SMC lineage and required for SMC contraction and regulation of blood pressure under adult physiologic conditions [40]. However, in response to vascular injury or within atherosclerotic lesions, VSMCs exhibit decreased expression of SMC marker proteins and increased migration, proliferation, and the production of extracellular matrix components Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry as well as matrix metalloproteinases [4].…”

Section: Discussionmentioning

confidence: 99%

Novel Zinc Finger Transcription Factor ZFP580 Facilitates All-Trans Retinoic Acid -Induced Vascular Smooth Muscle Cells Differentiation by Rarα-Mediated PI3K/Akt and ERK Signaling

Wei

Zhang

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phenotypic switching of vascular smooth muscle cells (VSMC) plays a vital role in the development of vascular diseases. All-trans retinoic acid (ATRA) is known to regulate VSMC phenotypes. However, the underlying mechanisms remain completely unknown. Here, we have investigated the probable roles and underlying mechanisms of the novel C2H2 zinc finger transcription factor ZFP580 on ATRA-induced VSMC differentiation. Methods: VSMCs were isolated, cultured, and identified. VSMCs were infected with an adenovirus encoding ZFP580 or Ad-siRNA to silence ZFP580. The expression levels of ZFP580, SMα-actin, SM22α, SMemb, RARα, RARβ, and RARγ were assayed by Q-PCR and western blot. A rat carotid artery injury model and morphometric analysis of intimal thickening were also used in this study. Results: ATRA caused a significant reduction of VSMC proliferation and migration in a doseand time-dependent manner. Moreover, it promoted VSMC differentiation by enhancing expression of differentiation markers and reducing expression of dedifferentiation markers. This ATRA activity was accompanied by up-regulation of ZFP580, with concomitant increases in RARα expression. In contrast, silencing of the RARα gene or inhibiting RARα with its antagonist Ro41-5253 abrogated the ATRA-induced ZFP580 expression. Furthermore, ATRA binding to RARα induced ZFP580 expression via the PI3K/Akt and ERK pathways. Adenovirusmediated overexpression of ZFP580 promoted VSMC differentiation by enhancing expression of SM22α and SMα-actin and reducing expression of SMemb. In contrast, silencing ZFP580 dramatically reduced the expression of differentiation markers and increased expression of dedifferentiation markers. The classic rat carotid artery balloon injury model demonstrated that ZFP580 inhibited proliferation and intimal hyperplasia in vivo. Conclusion: The novel zinc finger transcription factor ZFP580 facilitates ATRA-induced VSMC differentiation by the RARα-mediated PI3K/Akt and ERK signaling pathways. This might represent a novel mechanism of regulation of ZFP580 by ATRA and RARα, which is critical for understanding the biological functions of retinoids during VSMC phenotypic modulation.

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“…M 1 , M 3 , and M 5 receptors are efficiently coupled through G q/11 proteins to phospholipase Cβ, producing the second messengers diacylglycerol and inositol triphosphate [6] . Although we have an recent update about the type and its role in a large number of physiological processes, such as the function of heart and smooth muscles, glandular secretion, release of neurotransmitters, gene expression and cognitive functions as learning and memory [7] . However, contraction of the guinea-pig isolated gallbladder mediating muscarinic receptor which belongs to the M 3 or M 4 subtype and which was characterized by subtype agonists and antagonists [8] .…”

Section: Muscarinic Receptorsmentioning

confidence: 99%