Flow-mediated endothelial mechanotransduction

Davies, Peter F.

doi:10.1152/physrev.1995.75.3.519

Cited by 2,506 publications

(2,150 citation statements)

References 367 publications

(432 reference statements)

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“…Although OSI was significant throughout the LV, the apex recorded significantly higher 3D and axial OSI than the base and midV (Table 1). High OSI in arteries is frequently associated with vascular pathologies 20, 21…”

Section: Resultsmentioning

confidence: 99%

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

McCormick

Manduchi

Witschey

et al. 2016

JAHA

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BackgroundUnlike arteries, in which regionally distinct hemodynamics are associated with phenotypic heterogeneity, the relationships between endocardial endothelial cell phenotype and intraventricular flow remain largely unexplored. We investigated regional differences in left ventricular wall shear stress and their association with endocardial endothelial cell gene expression.Methods and ResultsLocal wall shear stress was calculated from 4‐dimensional flow magnetic resonance imaging in 3 distinct regions of human (n=8) and pig (n=5) left ventricle: base, adjacent to the outflow tract; midventricle; and apex. In both species, wall shear stress values were significantly lower in the apex and midventricle relative to the base; oscillatory shear index was elevated in the apex. RNA sequencing of the endocardial endothelial cell transcriptome in pig left ventricle (n=8) at a false discovery rate ≤10% identified 1051 genes differentially expressed between the base and the apex and 327 between the base and the midventricle; no differentially expressed genes were detected at this false discovery rate between the apex and the midventricle. Enrichment analyses identified apical upregulation of genes associated with translation initiation including mammalian target of rapamycin, and eukaryotic initiation factor 2 signaling. Genes of mitochondrial dysfunction and oxidative phosphorylation were also consistently upregulated in the left ventricular apex, as were tissue factor pathway inhibitor (mean 50‐fold) and prostacyclin synthase (5‐fold)—genes prominently associated with antithrombotic protection.ConclusionsWe report the first spatiotemporal measurements of wall shear stress within the left ventricle and linked regional hemodynamics to heterogeneity in ventricular endothelial gene expression, most notably to translation initiation and anticoagulation properties in the left ventricular apex, in which oscillatory shear index is increased and wall shear stress is decreased.

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Section: Resultsmentioning

confidence: 99%

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

McCormick

Manduchi

Witschey

et al. 2016

JAHA

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“…In addition, by using both RRBS and mRNA‐Seq, we discovered a set of mechanosensitive genes whose expression correlates to gene promoter DNA methylation status. Gene ontology analysis of these genes identified a number of pathways crucial for EC mechanotransduction and arteriogenesis, including several metabolism, transcription, MAPK signaling, and cell transport pathways 31, 66. Of note, SIRT4 was involved in a number of these significantly overrepresented pathways (Figure S5).…”

Section: Discussionmentioning

confidence: 99%

“…HUVECs are both phenotypically consistent and one of the most extensively used cell culture models for study of flow‐mediated EC signaling, including numerous studies of flow responses of the arterial system17, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 (eg, atheroprone versus atheroprotective waveforms) and DNMT1‐dependent DNA methylation 17, 18. For each set of experimental comparisons, cells were used from the same cell line between subculture passages 2 to 3.…”

Section: Methodsmentioning

confidence: 99%

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

Heuslein

Gorick

Song

et al. 2017

JAHA

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BackgroundArteriogenesis 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 ResultsIn 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.ConclusionsIncreased 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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“…3D bloodflow measurements covering the entire thoracic aorta were performed using time-resolved 3D CINE phase contrast (PC) MRI (flow-sensitive 4D-MRI). Data were acquired using an eight-channel body phased-array coil and a radio frequency (RF) spoiled gradient-echo sequence with interleaved three-directional velocity encoding (bandwidth ϭ Ϯ480 Hz/pixel, flip angle ϭ 15°, TE/TR ϭ 3.67 msec/6.1 msec, venc ϭ 150 cm/second, spatial resolution ϭ (2.71-2.93 ϫ 1.58 -1.69 ϫ 2.60 -3.0) mm 3 , and temporal resolution ϭ 48.8 msec, allowing for 11-15 time frames/cardiac cycle. All measurements were prospectively gated to the electrocardiogram (ECG) cycle and utilized an adaptive navigator gating to enable free breathing, as described previously (27).…”

Section: Mrimentioning

confidence: 99%

“…These forces can be characterized by wall shear stress (WSS) or oscillatory shear index (OSI) that play an important role in flow-mediated atherogenesis and arterial remodeling (1)(2)(3). While WSS values reported in the literature typically reflect the time-averaged shear forces acting on the vessel wall, OSI describes the existence and magnitude of WSS changes over the cardiac cycle.…”

mentioning

confidence: 99%

Three‐dimensional analysis of segmental wall shear stress in the aorta by flow‐sensitive four‐dimensional‐MRI

Frydrychowicz

Stalder

Russe

et al. 2009

Magnetic Resonance Imaging

165

138

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Purpose:To assess the distribution and regional differences of flow and vessel wall parameters such as wall shear stress (WSS) and oscillatory shear index (OSI) in the entire thoracic aorta. Materials and Methods:Thirty-one healthy volunteers (mean age ϭ 23.7 Ϯ 3.3 years) were examined by flow-sensitive four-dimensional (4D)-MRI at 3T. For eight retrospectively positioned 2D analysis planes distributed along the thoracic aorta, flow parameters and vectorial WSS and OSI were assessed in 12 segments along the vascular circumference. Conclusion:The normal distribution of vectorial WSS and OSI in the entire thoracic aorta derived from flow-sensitive 4D-MRI data provides a reference constituting an important perquisite for the examination of patients with aortic disease. Marked regional differences in absolute WSS and OSI may help explaining why atherosclerotic lesions predominantly develop and progress at specific locations in the aorta. COMPLEX VASCULAR GEOMETRY AND PULSATILE FLOW in the human arterial system lead to regionally different flow characteristics and thus spatial and temporal changes in shear forces acting on the vessel wall. These forces can be characterized by wall shear stress (WSS) or oscillatory shear index (OSI) that play an important role in flow-mediated atherogenesis and arterial remodeling (1-3). While WSS values reported in the literature typically reflect the time-averaged shear forces acting on the vessel wall, OSI describes the existence and magnitude of WSS changes over the cardiac cycle. Recent reports stressed the importance of WSS and OSI with respect to the formation and stability of atherosclerotic plaques (4). A number of studies have shown that low WSS and high OSI represent sensitive markers for formation of plaques in the aorta, carotid, or coronary arteries (5,6). Particularly, the assessment of both WSS and OSI can help to determine the complexity of the lesions. A recent study with animal models and deliberately altered flow characteristics in the carotid arteries demonstrated the close correlation of low WSS with the development of vulnerable high-risk plaques whereas high OSI induce stable lesions (4). In addition, the effects of selected pathologies on regionally-varying WSS and OSI values have been reported (7,8).Among other methods, MRI is a feasible and extensively validated technique to derive quantitative flow information from arterial vessels (9 -12). Due to its intrinsic sensitivity to flow and the possibility to acquire true time-resolved three-dimensional (3D) data, in vivo analyses of blood-flow and derived vessel wall parameters are promising. However, earlier reports on MRbased analysis of aortic hemodynamics were either based on incomplete vascular coverage and separately acquired 2D slices (13-17), a combination of MR mea-

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Flow-mediated endothelial mechanotransduction

Cited by 2,506 publications

References 367 publications

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

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

Three‐dimensional analysis of segmental wall shear stress in the aorta by flow‐sensitive four‐dimensional‐MRI

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