Estrogen-induced redox sensitive Id3 signaling controls the growth of vascular cells

Felty, Quentin; Porther, Nicole

doi:10.1016/j.atherosclerosis.2007.12.048

Cited by 31 publications

(38 citation statements)

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“…We previously reported that neovascularization mediated by 17β-estradiol (E2) exposure of HUVECs was dependent on ID3 (Felty and Porther, N.2008). In this study we have extended those findings with the human brain capillary endothelial cell line, hCMEC/D3 (Weksler et al 2005).…”

Section: Resultsmentioning

confidence: 99%

“…This type of Id interaction was reported to regulate transcription in a dominant-negative manner (Norton2000); however, besides the negative regulation of cell differentiation, Id proteins are also positive regulators of cell growth and play a major role in neovascularization. We have previously shown that ID3 is an important determinant of cell proliferation of estrogen treated HUVECs (Felty and Porther, N.2008). Since ID3 has been implicated in vascular lesion formation (Forrest et al 2004a; Matsumura et al 2001; Nickenig et al 2002), we hypothesize that ID3 is involved in the development of microvascular lesions in response to estrogen.…”

Section: Introductionmentioning

confidence: 99%

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Microvascular Lesions by Estrogen-Induced ID3: Its Implications in Cerebral and Cardiorenal Vascular Disease

Das

Felty

2014

J Mol Neurosci

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Severe symptoms of cerebral and cardiorenal vascular diseases can be triggered when cerebral, coronary, or glomerular arterioles grow inappropriately as a result of abnormal cell proliferation. The risk factor(s) and molecular mechanisms responsible for microvascular lesion formation are largely unknown. Although controversial, both animal and epidemiological studies have shown that estrogen increases the risk of stroke which may be due to microvascular lesions. Since microvascular diseases are characterized by excessive vessel growth, it is plausible that estrogen-induced neovascularization contributes to the growth of microvascular lesions. We present evidence for how ID3 overexpression in endothelial cells contributes to the development of an estrogen-induced neovascular phenotype with an additional focus on Pyk2 kinase. Our data showed that ID3 overexpression increased neovascularization, cell migration, and spheroid growth of human cerebral microvascular endothelial cells, hCMEC/D3. ID3 overexpressing cells showed significant estrogen-induced G2/M phase transition. Estrogen treatment increased both ID3 phosphorylation and total protein that was inhibited by tamoxifen; and Pyk2 mediated estrogen-induced ID3 mRNA expression. These findings suggest that Pyk2 signals ID3 expression and ID3 is necessary for estrogen-induced neovascularization in hCMEC/D3 cells. A better understanding of how microvascular lesions depend on ID3 may open new avenues for prevention and treatment of neurological diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microvascular Lesions by Estrogen-Induced ID3: Its Implications in Cerebral and Cardiorenal Vascular Disease

Das

Felty

2014

J Mol Neurosci

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“…The first gene, 242 kb upstream from BTA-49769-no-rs, was 'Bos taurus inhibitor of DNA binding 3, dominant negative helix-loop-helix protein' (ID3), which controls the growth of vascular cells through signalling that is induced by oestrogen (Felty and Porther, 2008). However, studies that have attempted to relate mutations in the ID3 gene to fertility in cattle were not found.…”

Section: Genetic Parametersmentioning

confidence: 99%

Genome-wide associations for fertility traits in Holstein–Friesian dairy cows using data from experimental research herds in four European countries

Berry

Bastiaansen

Veerkamp

et al. 2012

Animal

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Genome-wide association studies for difficult-to-measure traits are generally limited by the sample population size with accurate phenotypic data. The objective of this study was to utilise data on primiparous Holstein-Friesian cows from experimental farms in Ireland, the United Kingdom, the Netherlands and Sweden to identify genomic regions associated with traditional measures of fertility, as well as a fertility phenotype derived from milk progesterone profiles. Traditional fertility measures investigated were days to first heat, days to first service, pregnancy rate to first service, number of services and calving interval (CI); post-partum interval to the commencement of luteal activity (CLA) was derived using routine milk progesterone assays. Phenotypic and genotypic data on 37 590 single nucleotide polymorphisms (SNPs) were available for up to 1570 primiparous cows. Genetic parameters were estimated using linear animal models, and univariate and bivariate genome-wide association analyses were undertaken using Bayesian stochastic search variable selection performed using Gibbs sampling. Heritability estimates of the traditional fertility traits varied from 0.03 to 0.16; the heritability for CLA was 0.13. The posterior quantitative trait locus (QTL) probabilities, across the genome, for the traditional fertility measures were all ,0.021. Posterior QTL probabilities of 0.060 and 0.045 were observed for CLA on SNPs each on chromosome 2 and chromosome 21, respectively, in the univariate analyses; these probabilities increased when CLA was included in the bivariate analyses with the traditional fertility traits. For example, in the bivariate analysis with CI, the posterior QTL probability of the two aforementioned SNPs were 0.662 and 0.123. Candidate genes in the vicinity of these SNPs are discussed. The results from this study suggest that the power of genome-wide association studies in cattle may be increased by sharing of data and also possibly by using physiological measures of the trait under investigation.Keywords: genome-wide association, fertility, cow, progesterone ImplicationsTraditional genetic selection for fertility is made difficult by the low heritability of traditional fertility phenotypes. This limitation can be minimised by increasing the heritability of the trait(s) or by using genomic information that explains a large proportion of the genetic variation in fertility. In the present study, both approaches were investigated. Heritability estimates greater than some traditional fertility traits were observed for the post-partum commencement of luteal activity quantified using milk progesterone concentration. Specific regions of the genome associated with fertility were also observed, albeit they only explained a small proportion of the total genetic variance in the traits.

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“…We have previously shown that ID3 is an important determinant of ROS-induced proliferation of estrogen exposed ECs [10], however, the effect of environmental PCBs on Id proteins has not been investigated until now. The Id (inhibitors of DNA binding and differentiation) family of proteins family of proteins consists of four genes (Id1–Id4).…”

Section: Introductionmentioning

confidence: 99%

PCB153-Induced Overexpression of ID3 Contributes to the Development of Microvascular Lesions

Das

Felty

2014

PLoS ONE

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Microvascular lesions resulting from endothelial cell dysfunction are produced in the brain, lung, kidney, and retina of patients of complex chronic diseases. The environmental and molecular risk factors which may contribute in the development of microvascular damage are unclear. The mechanism(s) responsible for initiating microvascular damage remain poorly defined, although several inciting factors have been proposed, including environmental toxicants-induced oxidative stress. Enhanced neovascularization has been implicated in either the development or progression of proliferative vascular lesions. Here, we present evidence for how PCB-induced ROS may contribute to the development of a neovascular phenotype with the aim of elucidating the role of environmental toxicants in endothelial dysfunction with a specific focus on the inhibitor of differentiation protein ID3. We used a combination of phenotype and immunohistochemical analysis followed by validating with protein expression and post-translational modifications with Western Blot and MALDI-TOF/TOF analysis. We also looked for a correlation between ID3 expression in vascular tissue. Our results showed that PCB-induced ROS mediated a highly tube branched neovascular phenotype that also depended on ID3 and Pyk2; and PCB153 treatment increased the size of endothelial spheroids under conditions typically used for clonal selection of stem cell spheroids. High ID3 protein expression correlated with a greater degree of malignancy and oxidative DNA damage marker 8-OHdG in blood vessels from human subjects. PCB153 treatment increased both serine and tyrosine phosphorylation of endothelial ID3. Stable ID3 overexpression increased cell survival of human microvascular endothelial cell line hCMEC/D3. In summary, our data provide evidence that ID3 may play a critical role in regulating vascular endothelial cell survival and development of microvascular lesions induced by persistent environmental pollutants such as PCB153. Findings of this study are important because they provide a new paradigm by which PCBs may contribute to the growth of microvascular lesions.

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Estrogen-induced redox sensitive Id3 signaling controls the growth of vascular cells

Cited by 31 publications

References 38 publications

Microvascular Lesions by Estrogen-Induced ID3: Its Implications in Cerebral and Cardiorenal Vascular Disease

Microvascular Lesions by Estrogen-Induced ID3: Its Implications in Cerebral and Cardiorenal Vascular Disease

Genome-wide associations for fertility traits in Holstein–Friesian dairy cows using data from experimental research herds in four European countries

PCB153-Induced Overexpression of ID3 Contributes to the Development of Microvascular Lesions

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