Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Pinna, Christian; Bolego, Chiara; Sanvito, Paola; Pelosi, V.; Baetta, Roberta; Corsini, Alberto; Gaion, R.M.; Cignarella, Andrea

doi:10.1124/jpet.106.106062

Cited by 15 publications

(10 citation statements)

References 45 publications

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“…Clinical and animal studies have suggested multiple benefits of SERM, and several SERMs have already been clinically approved, including raloxifene and tamoxifen. Recent findings have demonstrated the beneficial effects of these two classical SERMs upon the vascular system [52], [53], [54], [55]. Since raloxifene and tamoxifen share the same/similar antagonistic action with calycosin at ERβ, we compared the angiogenic effects of the three compounds in zebrafish embryos.…”

Section: Discussionmentioning

confidence: 99%

Calycosin Promotes Angiogenesis Involving Estrogen Receptor and Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Zebrafish and HUVEC

Tang

et al. 2010

PLoS ONE

114

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BackgroundAngiogenesis plays an important role in a wide range of physiological processes, and many diseases are associated with the dysregulation of angiogenesis. Radix Astragali is a Chinese medicinal herb commonly used for treating cardiovascular disorders and has been shown to possess angiogenic effect in previous studies but its active constituent and underlying mechanism remain unclear. The present study investigates the angiogenic effects of calycosin, a major isoflavonoid isolated from Radix Astragali, in vitro and in vivo.Methodology Tg(fli1:EGFP) and Tg(fli1:nEGFP) transgenic zebrafish embryos were treated with different concentrations of calycosin (10, 30, 100 µM) from 72 hpf to 96 hpf prior morphological observation and angiogenesis phenotypes assessment. Zebrafish embryos were exposed to calycosin (10, 100 µM) from 72 hpf to 78 hpf before gene-expression analysis. The effects of VEGFR tyrosine kinase inhibitor on calycosin-induced angiogenesis were studied using 72 hpf Tg(fli1:EGFP) and Tg(fli1:nEGFP) zebrafish embryos. The pro-angiogenic effects of calycosin were compared with raloxifene and tamoxifen in 72 hpf Tg(fli1:EGFP) zebrafish embryos. The binding affinities of calycosin to estrogen receptors (ERs) were evaluated by cell-free and cell-based estrogen receptor binding assays. Human umbilical vein endothelial cell cultures (HUVEC) were pretreated with different concentrations of calycosin (3, 10, 30, 100 µM) for 48 h then tested for cell viability and tube formation. The role of MAPK signaling in calycosin-induced angiogenesis was evaluated using western blotting.ConclusionCalycosin was shown to induce angiogenesis in human umbilical vein endothelial cell cultures (HUVEC) in vitro and zebrafish embryos in vivo via the up-regulation of vascular endothelial growth factor (VEGF), VEGFR1 and VEGFR2 mRNA expression. It was demonstrated that calycosin acted similar to other selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, by displaying selective potency and affinity to estrogen receptors ERα and ERβ. Our results further indicated that calycosin promotes angiogenesis via activation of MAPK with the involvement of ERK1/2 and ER. Together, this study revealed, for the first time, that calycosin acts as a selective estrogen receptor modulator (SERM) to promote angiogenesis, at least in part through VEGF-VEGFR2 and MAPK signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Calycosin Promotes Angiogenesis Involving Estrogen Receptor and Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Zebrafish and HUVEC

Tang

et al. 2010

PLoS ONE

114

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“…GPER is also expressed in non-endothelial vascular cells, such as smooth muscle cells (Haas et al, 2007; Isensee et al, 2009), being expressed in both human arteries and veins and being regulated in response to estrogen (Haas et al, 2007). Non-genomic vasodilator effects have been described for estrogen (a non-selective estrogen receptor agonist) and phytoestrogens (such as genestein) as well as antagonists of the “classical” estrogen receptors (ICI182,780) and SERMs (such as tamoxifen and raloxifene) (Leung et al, 2007; Meyer et al, 2009; Pinna et al, 2006). For many years, the relaxant effects of the latter remained unexplained mechanistically.…”

Section: Physiological Functions Of Gper As An Estrogen Receptormentioning

confidence: 99%

Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER

Prossnitz

Barton

2009

Prostaglandins & Other Lipid Mediators

145

109

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GPR30, now named GPER1 (G protein-coupled estrogen receptor1) or GPER here, was first identified as an orphan 7-transmembrane G protein-coupled receptor by multiple laboratories using either homology cloning or differential expression and subsequently shown to be required for estrogen-mediated signaling in certain cancer cells. The actions of estrogen are extensive in the body and are thought to be mediated predominantly by classical nuclear estrogen receptors that act as transcription factors/regulators. Nevertheless, certain aspects of estrogen function remain incompatible with the generally accepted mechanisms of classical estrogen receptor action. Many recent studies have revealed that GPER contributes to some of the actions of estrogen, including rapid signaling events and rapid transcriptional activation. With the introduction of GPER-selective ligands and GPER knockout mice, the functions of GPER are becoming more clearly defined. In many cases, there appears to be a complex interplay between the two receptor systems, suggesting that estrogen-mediated physiological responses may be mediated by either receptor or a combination of both receptor types, with important medical implications.

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“…Similarly, raloxifene elicits rapid endothelium-dependent nitric oxide-mediated vasorelaxation in rat aorta that is not sensitive to either the nonselective ER antagonist ICI 182,780 or the selective ERα antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5- (4-(2-piperidinylethoxy) phenol)-1H-pyrazole (MPP) [38]. Raloxifene also elicits long-term anti-inflammatory actions in rat aortic VSM cells via upregulation of ERα protein levels [39]. …”

Section: Modulators Of Vascular Ersmentioning

confidence: 99%

Experimental Benefits of Sex Hormones on Vascular Function and the Outcome of Hormone Therapy in Cardiovascular Disease

Ross¹,

Serock²,

Khalil³

2008

CCR

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Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation. However, the experimental evidence did not translate into vascular benefits of hormone replacement therapy (HRT) in postmenopausal women, and HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events with HRT. The lack of vascular benefits of HRT could be related to the hormone used, the vascular estrogen receptor (ER), and the subject’s age and preexisting cardiovascular condition. Natural and phytoestrogens in small doses may be more beneficial than synthetic estrogen. Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer. Transdermal estrogens avoid the first-pass liver metabolism associated with the oral route. Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT. Variants of cytosolic/nuclear ER mediate transcriptional genomic effects that stimulate endothelial cell growth, but inhibit vascular smooth muscle (VSM) proliferation. Also, plasma membrane ERs trigger not only non-genomic stimulation of endothelium-dependent vascular relaxation, but also inhibition of [Ca2+]i, protein kinase C and Rho kinase-dependent VSM contraction. HRT could also be more effective in the perimenopausal period than in older postmenopausal women, and may prevent the development, while worsening preexisting CVD. Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations. Thus, the type, dose, route of administration and the timing/duration of HRT should be customized depending on the subject’s age and preexisting cardiovascular condition, and thereby make it possible to translate the beneficial vascular effects of sex hormones to the outcome of HRT in postmenopausal CVD.

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Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Cited by 15 publications

References 45 publications

Calycosin Promotes Angiogenesis Involving Estrogen Receptor and Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Zebrafish and HUVEC

Calycosin Promotes Angiogenesis Involving Estrogen Receptor and Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Zebrafish and HUVEC

Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER

Experimental Benefits of Sex Hormones on Vascular Function and the Outcome of Hormone Therapy in Cardiovascular Disease

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