Regulation of vascular smooth muscle cell differentiation

Rzucidlo, Eva M.; Martin, Kathleen A.; Powell, Richard J.

doi:10.1016/j.jvs.2007.03.001

Cited by 343 publications

(275 citation statements)

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“…The synthetic phenotype is characterized by a high rate of cell proliferation and migration and decreased expression of contractile proteins 24, 54, 55, 56, 57. Disruption of the balance of the VSMCs phenotypes (for example, a transition from a contractile phenotype to a synthetic phenotype) will favor VSMCs proliferation and migration, leading to development of neointimal formation and restenosis after vascular injury 24, 55, 56, 57, 58. Immunostaining showed that 28 days after the surgery, vascular injury significantly reduced the expression levels of α‐SMA, SM22, and MYH11 in the WT group compared with the sham group, and further reduced α‐SMA, SM22, and MYH11 expression in the AGGF1 +/− KO mice (Figure 5A and 5B).…”

Section: Resultsmentioning

confidence: 99%

“…The SRF is a key transcription factor for phenotypic switching of VSMCs by binding to the promoter/regulatory regions of VSMCs‐specific contractile genes, specifically to the cis‐acting DNA sequence CArG box (CC[A/T]6GG), to induce their expression 55, 56, 57, 58. Western blots and real‐time PCR analyses showed that although AGGF1 protein treatment can reverse downregulation of contractile genes/proteins α‐SMA, SM22, and MYH11 by PDGF‐BB in VSMCs, but the effects were completely lost in cells with knockdown of SRF expression by small interfering RNA (+siSRF) (Figure 6G and 6H).…”

Section: Resultsmentioning

confidence: 99%

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Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Yao

et al. 2017

JAHA

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BackgroundDespite recent improvements in angioplasty and placement of drug‐eluting stents in treatment of atherosclerosis, restenosis and in‐stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury.Methods and Results AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/− mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet‐derived growth factor‐BB–induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs to the synthetic phenotype by countering the inhibitory effect of platelet‐derived growth factor‐BB on SRF expression and the formation of the myocardin/SRF/CArG‐box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet‐derived growth factor‐BB–induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1.Conclusions AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1‐MEK1/2‐ERK1/2‐Elk‐myocardin‐SRF/p27 signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Yao

et al. 2017

JAHA

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“…Recent studies suggest that VSMCs play a central role in the development and progression of atherosclerosis 3. During the development of atherosclerosis, VSMCs change from a contractile phenotype to a synthetic phenotype, migrate to the intima, increase their proliferative ability and promote the synthesis of extracellular matrix proteins 4, 5.…”

Section: Introductionmentioning

confidence: 99%

“…During the development of atherosclerosis, VSMCs change from a contractile phenotype to a synthetic phenotype, migrate to the intima, increase their proliferative ability and promote the synthesis of extracellular matrix proteins 4, 5. VSMCs exhibit a contractile phenotype characterized by the expression of contractile marker such as α‐SMA and synthetic phenotype characterized by the expression of synthetic marker osteopontin (OPN) 3, 6. Therefore, the regulation of the VSMC phenotype may be an alternative strategy for effective atherosclerosis prevention and treatment.…”

Section: Introductionmentioning

confidence: 99%

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

Pan

Liu

Gao

et al. 2018

J Cellular Molecular Medi

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Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low‐density lipoprotein receptor‐deficient (LDLR−/−) mice and to elucidate the molecular processes underlying this effect. LDLR−/− mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α‐actin (α‐SMA) antibodies and anti‐osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α‐SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high‐fat‐fed LDLR−/− mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.

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“…9 It was well established that the phenotypic modulation within vascular SM cells has a critical role in the pathogenesis of a variety of cardiovascular diseases such as diabetic vascular complication, atherosclerosis, hypertension and transplantation arteriopathy. 8,10 As the penis is considered as an extension of the vascular system, 11 it is not surprising to suppose that many changes of the cardiovascular system could also be found within the corporal tissue. However, to the best of our knowledge, the characteristics of the phenotypic modulation within CCSM cells under hyperglycemic conditions in diabetic rats were not well elucidated.…”

Section: Introductionmentioning

confidence: 99%

Characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction

et al. 2012

Int J Impot Res

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Phenotypic modulation from a contractile to a proliferative state within vascular smooth muscle cells has a critical role in the pathogenesis of a variety of cardiovascular diseases. To investigate the characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction, a group of Sprague--Dawley rats (n ¼ 30) were induced by intraperitoneal injection of streptozotocin (60 mg kg À1 ) and screened by subcutaneous injection of apomorphine (100 mg kg À1 ) for the measurement and comparison of the penile erections, and then three different groups were defined. Primary corpus cavernosum smooth muscle cells were cultured and passaged. The cavernous tissue segments were subjected to quantitative real-time polymerase chain reaction to determine the expressions of smooth muscle a-actin (SMA), SM myosin heavy chain (SMMHC), smoothelin, calponin and myocardin. Cell contractility in vitro and western blot analysis of SMA and SMMHC in the cavernous tissues and cells were determined. Compared with the control group (n ¼ 8) and the diabetes mellitus group (n ¼ 5), the expressions of SMA, calponin, SMMHC, smoothelin and myocardin mRNA were decreased in the cavernous tissues in rats of the diabetic erectile dysfunction group (n ¼ 15; P ¼ 0.001 and 0.02, P ¼ 0.014 and 0.012, both Po0.001, P ¼ 0.005 and o0.001, P ¼ 0.003 and 0.035, respectively). The levels of SMA and SMMHC proteins showed a significant decrease in cavernous tissues and cultured cells in rats of the diabetic erectile dysfunction group. Cells of the diabetic erectile dysfunction group exhibited significantly less contractility compared with those of other groups (Po0.001). Corpus cavernosum SM cell possesses the ability to modulate the phenotype under hyperglycemic conditions, which could have a key role in the pathogenesis of diabetic erectile dysfunction. Keywords: diabetes mellitus; erectile dysfunction; smooth muscle INTRODUCTION Erectile dysfunction (ED), a distressing complication of diabetes mellitus (DM), 1 is three times more common in diabetic male rats than in non-diabetic male rats. It has been reported that about 35--90% of diabetic male rats suffer from ED. 2,3 The pathogenesis of DM-related ED may be involved in many aspects; however, it was well known that vascular causative factors contribute significantly. 4 Corpus cavernosum smooth muscle (CCSM), the structural basis of cavernous space relaxing and penile erection, has a key role in the change of hemodynamics during penile erection. CCSM cell relaxation mediated by parasympathetic neurotransmission, nitric oxide, electrophysiological events and possibly other regulatory factors is necessary for normal penile erection. 5 It has been observed that the CCSM cell mass was lost in diabetic rats with ED, and the remaining SM cells were unable to achieve sufficient relaxation to attain the high intracorporeal pressures that are necessary for the passive occlusion of the veins that egress the corporal bodies as they traverse underneath and through the tunica albu...

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Regulation of vascular smooth muscle cell differentiation

Cited by 343 publications

References 62 publications

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

Characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction

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