Limits...
Angiogenesis interactome and time course microarray data reveal the distinct activation patterns in endothelial cells.

Chu LH, Lee E, Bader JS, Popel AS - PLoS ONE (2014)

Bottom Line: Combining dynamic gene expression time-course data for stimulated EC with protein-protein interactions associated with angiogenesis (the "angiome") could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention.We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles.The results show that VEGFR1-VEGFR2 levels are more closely coupled than VEGFR1-VEGFR3 or VEGFR2-VEGFR3 in HUVEC and MEC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Angiogenesis involves stimulation of endothelial cells (EC) by various cytokines and growth factors, but the signaling mechanisms are not completely understood. Combining dynamic gene expression time-course data for stimulated EC with protein-protein interactions associated with angiogenesis (the "angiome") could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention. We constructed the protein-protein interaction networks of positive and negative regulation of angiogenesis comprising 367 and 245 proteins, respectively. We used five published gene expression datasets derived from in vitro assays using different types of blood endothelial cells stimulated by VEGFA (vascular endothelial growth factor A). We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles. The statistically significant patterns between 2D fibronectin and 3D type I collagen substrates for telomerase-immortalized EC (TIME) show that different substrates could influence the temporal gene activation patterns in the same cell line. We investigated the different activation patterns among 18 transmembrane tyrosine kinase receptors, and experimentally measured the protein level of the tyrosine-kinase receptors VEGFR1, VEGFR2 and VEGFR3 in human umbilical vein EC (HUVEC) and human microvascular EC (MEC). The results show that VEGFR1-VEGFR2 levels are more closely coupled than VEGFR1-VEGFR3 or VEGFR2-VEGFR3 in HUVEC and MEC. This computational methodology can be extended to investigate other molecules or biological processes such as cell cycle.

Show MeSH
Temporal gene expression profiles on 2D fibronectin and 3D collagen I for TIME cells in (A) and (B), respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4199761&req=5

pone-0110871-g002: Temporal gene expression profiles on 2D fibronectin and 3D collagen I for TIME cells in (A) and (B), respectively.

Mentions: We show the four statistically significant (adjusted p-value<0.05 by Bonferroni correction) temporal gene expression profiles of TIME cells on 2D fibronectin, and sort the four profiles by their p-values in Figure 2 (A). The p-value was calculated by the number of genes assigned to the model profile, compared to the expected number of assigned genes. The number on top left represents the assigned profile number by STEM, and the number on bottom left represents the significance level before the Bonferroni correction. The box is colored if the statistically significant number of genes, based on the adjusted p-value<0.05 by Bonferroni correction, are assigned to the model profile. The black and red lines in the individual profile boxes indicate the assigned pattern, e.g. the sequence (0,1,2,3,4,5,6,7,8) over the eight time points and initial points in profile #16, and the gene expression of genes assigned in that profile. We compare the four statistical significant profiles on 2D fibronectin in Figure 2 (A) with 3D type I collagen, and plot the four profiles (#16, #4, #5, #9) in Figure 2 (B). We found statistically significant patterns of continuous up- and down-regulation depicted by profiles #16 and #4 (shown on the top-left corner of each profile box) exist for both matrices on TIME cells, but fluctuation patterns depicted by profiles #5 and #9 are only exhibited on 2D fibronectin (Figure 2A).


Angiogenesis interactome and time course microarray data reveal the distinct activation patterns in endothelial cells.

Chu LH, Lee E, Bader JS, Popel AS - PLoS ONE (2014)

Temporal gene expression profiles on 2D fibronectin and 3D collagen I for TIME cells in (A) and (B), respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199761&req=5

pone-0110871-g002: Temporal gene expression profiles on 2D fibronectin and 3D collagen I for TIME cells in (A) and (B), respectively.
Mentions: We show the four statistically significant (adjusted p-value<0.05 by Bonferroni correction) temporal gene expression profiles of TIME cells on 2D fibronectin, and sort the four profiles by their p-values in Figure 2 (A). The p-value was calculated by the number of genes assigned to the model profile, compared to the expected number of assigned genes. The number on top left represents the assigned profile number by STEM, and the number on bottom left represents the significance level before the Bonferroni correction. The box is colored if the statistically significant number of genes, based on the adjusted p-value<0.05 by Bonferroni correction, are assigned to the model profile. The black and red lines in the individual profile boxes indicate the assigned pattern, e.g. the sequence (0,1,2,3,4,5,6,7,8) over the eight time points and initial points in profile #16, and the gene expression of genes assigned in that profile. We compare the four statistical significant profiles on 2D fibronectin in Figure 2 (A) with 3D type I collagen, and plot the four profiles (#16, #4, #5, #9) in Figure 2 (B). We found statistically significant patterns of continuous up- and down-regulation depicted by profiles #16 and #4 (shown on the top-left corner of each profile box) exist for both matrices on TIME cells, but fluctuation patterns depicted by profiles #5 and #9 are only exhibited on 2D fibronectin (Figure 2A).

Bottom Line: Combining dynamic gene expression time-course data for stimulated EC with protein-protein interactions associated with angiogenesis (the "angiome") could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention.We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles.The results show that VEGFR1-VEGFR2 levels are more closely coupled than VEGFR1-VEGFR3 or VEGFR2-VEGFR3 in HUVEC and MEC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Angiogenesis involves stimulation of endothelial cells (EC) by various cytokines and growth factors, but the signaling mechanisms are not completely understood. Combining dynamic gene expression time-course data for stimulated EC with protein-protein interactions associated with angiogenesis (the "angiome") could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention. We constructed the protein-protein interaction networks of positive and negative regulation of angiogenesis comprising 367 and 245 proteins, respectively. We used five published gene expression datasets derived from in vitro assays using different types of blood endothelial cells stimulated by VEGFA (vascular endothelial growth factor A). We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles. The statistically significant patterns between 2D fibronectin and 3D type I collagen substrates for telomerase-immortalized EC (TIME) show that different substrates could influence the temporal gene activation patterns in the same cell line. We investigated the different activation patterns among 18 transmembrane tyrosine kinase receptors, and experimentally measured the protein level of the tyrosine-kinase receptors VEGFR1, VEGFR2 and VEGFR3 in human umbilical vein EC (HUVEC) and human microvascular EC (MEC). The results show that VEGFR1-VEGFR2 levels are more closely coupled than VEGFR1-VEGFR3 or VEGFR2-VEGFR3 in HUVEC and MEC. This computational methodology can be extended to investigate other molecules or biological processes such as cell cycle.

Show MeSH