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Mechanical regulation of epigenetics in vascular biology and pathobiology.

Chen LJ, Wei SY, Chiu JJ - J. Cell. Mol. Med. (2013)

Bottom Line: The role of haemodynamic force-induced epigenetic modifications in the regulation of vascular gene expression and function has recently been elucidated.Through the studies of gene expression, cell proliferation, angiogenesis, migration and pathophysiological states, we present a conceptual framework for understanding how mechanical force-induced epigenetic modifications work to control vascular gene expression and function and, hence, the development of vascular disorders.This research contributes to our knowledge of how the mechanical environment impacts the chromatin state of ECs and VSMCs and the consequent cellular behaviours.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 350, Taiwan.

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Related in: MedlinePlus

Schematic diagram of miRNAs and their function in ECs in response to shear stress. Oscillatory flow induces the expression of miR-92a, miR-21 and miR-663, leading to the repression of KLF-2 and PPAR-α expressions and an inflammatory response in ECs. Laminar shear stress induces the expressions of miR-19a and miR-23b, resulting in cell cycle arrest in ECs.
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fig03: Schematic diagram of miRNAs and their function in ECs in response to shear stress. Oscillatory flow induces the expression of miR-92a, miR-21 and miR-663, leading to the repression of KLF-2 and PPAR-α expressions and an inflammatory response in ECs. Laminar shear stress induces the expressions of miR-19a and miR-23b, resulting in cell cycle arrest in ECs.

Mentions: In current studies, the functions of haemodynamic force-induced miRNAs have been clarified in vascular cells (Fig. 3). These functions include angiogenesis, inflammation, proliferation and migration. The endothelium-specific transcription factor KLF-2 has been well-established to participate in the regulation of eNOS gene expression 80. A new regulatory circuit of KLF-2-mediated expression of eNOS by an RNA-based mechanism has been clarified 81. ECs that were subjected to oscillatory flow (0 ± 4 dyne/cm2), but not pulsatile flow (12 ± 4 dyne/cm2) were triggered to express miR-92a. Bioinformatics analysis demonstrated that KLF-2 is a target gene of miR-92a, and its gene and protein expression levels are down-regulated in oscillatory shear-stimulated ECs. In addition, the KLF-2-regulated genes eNOS and thrombomodulin were repressed by the overexpression of miR-92a in ECs. Nicoli et al. used a zebrafish embryonic model to demonstrate that the angiogenic sprouting of blood vessels requires the blood flow-induced transcription factor KLF-2 82. KLF-2 acts upstream of miR-126 to promote fluid flow-stimulated angiogenesis through VEGF signalling. Co-injection of both morpholinos, resulting in the specific knockdown of KLF-2 and miR-126, caused a dramatic defect in the penetrance of AA5X. This implies that KLF-2 and miR-126 share a common pathway in modulating angiogenesis. This study provided new insights into how ECs respond to flow stress and integrate developmental signals with miR-126 to promote angiogenesis. On the other hand, laminar shear stress has been identified as a regulator of EC anti-proliferation as a result of miRNA modulation of cell cycle regulators. Qin and Wang et al. demonstrated that laminar shear stress induces miR-19a and miR-23b, which may participate in cell cycle regulation, leading to EC arrest at G1/S 83, 84.


Mechanical regulation of epigenetics in vascular biology and pathobiology.

Chen LJ, Wei SY, Chiu JJ - J. Cell. Mol. Med. (2013)

Schematic diagram of miRNAs and their function in ECs in response to shear stress. Oscillatory flow induces the expression of miR-92a, miR-21 and miR-663, leading to the repression of KLF-2 and PPAR-α expressions and an inflammatory response in ECs. Laminar shear stress induces the expressions of miR-19a and miR-23b, resulting in cell cycle arrest in ECs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3822644&req=5

fig03: Schematic diagram of miRNAs and their function in ECs in response to shear stress. Oscillatory flow induces the expression of miR-92a, miR-21 and miR-663, leading to the repression of KLF-2 and PPAR-α expressions and an inflammatory response in ECs. Laminar shear stress induces the expressions of miR-19a and miR-23b, resulting in cell cycle arrest in ECs.
Mentions: In current studies, the functions of haemodynamic force-induced miRNAs have been clarified in vascular cells (Fig. 3). These functions include angiogenesis, inflammation, proliferation and migration. The endothelium-specific transcription factor KLF-2 has been well-established to participate in the regulation of eNOS gene expression 80. A new regulatory circuit of KLF-2-mediated expression of eNOS by an RNA-based mechanism has been clarified 81. ECs that were subjected to oscillatory flow (0 ± 4 dyne/cm2), but not pulsatile flow (12 ± 4 dyne/cm2) were triggered to express miR-92a. Bioinformatics analysis demonstrated that KLF-2 is a target gene of miR-92a, and its gene and protein expression levels are down-regulated in oscillatory shear-stimulated ECs. In addition, the KLF-2-regulated genes eNOS and thrombomodulin were repressed by the overexpression of miR-92a in ECs. Nicoli et al. used a zebrafish embryonic model to demonstrate that the angiogenic sprouting of blood vessels requires the blood flow-induced transcription factor KLF-2 82. KLF-2 acts upstream of miR-126 to promote fluid flow-stimulated angiogenesis through VEGF signalling. Co-injection of both morpholinos, resulting in the specific knockdown of KLF-2 and miR-126, caused a dramatic defect in the penetrance of AA5X. This implies that KLF-2 and miR-126 share a common pathway in modulating angiogenesis. This study provided new insights into how ECs respond to flow stress and integrate developmental signals with miR-126 to promote angiogenesis. On the other hand, laminar shear stress has been identified as a regulator of EC anti-proliferation as a result of miRNA modulation of cell cycle regulators. Qin and Wang et al. demonstrated that laminar shear stress induces miR-19a and miR-23b, which may participate in cell cycle regulation, leading to EC arrest at G1/S 83, 84.

Bottom Line: The role of haemodynamic force-induced epigenetic modifications in the regulation of vascular gene expression and function has recently been elucidated.Through the studies of gene expression, cell proliferation, angiogenesis, migration and pathophysiological states, we present a conceptual framework for understanding how mechanical force-induced epigenetic modifications work to control vascular gene expression and function and, hence, the development of vascular disorders.This research contributes to our knowledge of how the mechanical environment impacts the chromatin state of ECs and VSMCs and the consequent cellular behaviours.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 350, Taiwan.

Show MeSH
Related in: MedlinePlus