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DNA Methyltransferase 1-Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point.

DNA Methyltransferase 1-Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point.
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Heuslein JL, Gorick CM, Song J, Price RJ,


Heuslein JL, Gorick CM, Song J, Price RJ, (click to view)

Heuslein JL, Gorick CM, Song J, Price RJ,

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Journal of the American Heart Association 2017 11 306(12) pii e007673
Abstract
BACKGROUND
Arteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original "set point." However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)-dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.

METHODS AND RESULTS
In femoral artery ligation-operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5-methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed-flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome-wide hypermethylation of gene promoters, and a DNMT1-dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed-flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation-operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.

CONCLUSIONS
Increased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1-dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.

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