Vascular Endothelial Morphology as an Indicator of the Pattern of Blood Flow

Nerem, Robert M.; Levesque, M. J.; Cornhill, J. Fredrick

doi:10.1115/1.3138275

Cited by 285 publications

(148 citation statements)

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“…In contrast, cells in disturbed flow do not align, Klf2 and Klf4 remain low (36, 37), and NF-κB and other inflammatory pathways remain high (22,23,34). Poor endothelial alignment is also a marker for susceptibility to atherosclerosis in vivo (38).…”

Section: Discussionmentioning

confidence: 99%

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Baeyens

Mulligan-Kehoe

Corti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

134

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Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4 −/− ) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4 −/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis. mechanotransduction | polarity | shear stress | atherosclerosis S yndecan 4 (S4) is a transmembrane heparan sulfate proteoglycan that serves as a coreceptor for extracellular matrix proteins and growth factors (1-3). S4−/− mice are viable and fertile (4, 5) but show defective wound healing consequent to impaired angiogenesis (6). They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9-11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).Atherosclerosis is an inflammatory disease of large to midsized arteries that is the major cause of illness and death in developed nations and is rapidly increasing in developing nations (14,15). It is linked to a variety of risk factors including high LDL cholesterol level and triglycerides, diabetes, smoking, hypertension, sedentary lifestyle, and inflammatory mediators. However, atherosclerotic lesions occur selectively in regions of arteries that are subject to disturbances in fluid shear stress (FSS), the frictional force flowing blood exerts on the endothelium. Regions of arteries with lower flow magnitude, flow reversal, and other complex spatial/ temporal flow patterns are predisposed to atherosclerosis. Systemic risk factors appear to synergize with local biomechanical factors in the initiation and progression of atherosclerotic lesions (16).The importance of S4 in endothelial bi...

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Section: Discussionmentioning

confidence: 99%

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Baeyens

Mulligan-Kehoe

Corti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

134

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“…Endothelial cells (ECs) are sensitive to temporal shear gradients 5,6,17 and spatial shear gradients, 14 the nature of which is thought to determine whether ECs exhibit an atherogenic or atheroprotective phenotype. 37 Shear stress also plays a major role in the coordination of blood flow in the microvasculature 6,31 and, hence, in the maintenance of capillary blood pressure, and the delivery of oxygen, nutrients and immunity-related leucocytes to the tissue.…”

Section: Introductionmentioning

confidence: 99%

Finite-Element Stress Analysis of a Multicomponent Model of Sheared and Focally-Adhered Endothelial Cells

et al. 2007

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Hemodynamic forces applied at the apical surface of vascular endothelial cells may be redistributed to and amplified at remote intracellular organelles and protein complexes where they are transduced to biochemical signals. In this study we sought to quantify the effects of cellular material inhomogeneities and discrete attachment points on intracellular stresses resulting from physiological fluid flow. Steady-state shear-and magnetic bead-induced stress, strain, and displacement distributions were determined from finite-element stress analysis of a cell-specific, multicomponent elastic continuum model developed from multimodal fluorescence images of confluent endothelial cell (EC) monolayers and their nuclei. Focal adhesion locations and areas were determined from quantitative total internal reflection fluorescence microscopy and verified using green fluorescence protein-focal adhesion kinase (GFP-FAK). The model predicts that shear stress induces small heterogeneous deformations of the endothelial cell cytoplasm on the order of <100 nm. However, strain and stress were amplified 10-100-fold over apical values in and around the high-modulus nucleus and near focal adhesions (FAs) and stress distributions depended on flow direction. The presence of a 0.4 μm glycocalyx was predicted to increase intracellular stresses by ~2-fold. The model of magnetic bead twisting rheometry also predicted heterogeneous stress, strain, and displacement fields resulting from material heterogeneities and FAs. Thus, large differences in moduli between the nucleus and cytoplasm and the juxtaposition of constrained regions (e.g. FAs) and unattached regions provide two mechanisms of stress amplification in sheared endothelial cells. Such phenomena may play a role in subcellular localization of early mechanotransduction events.

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“…Parameters were calculated using NIH Image analysis software (version 1.62). The following 4 parameters were evaluated morphometrically: (1) size of cardiomyocytes: the short diameter of the cardiomyocytes was measured at the nuclear level in 75 cells randomly selected from 5 photomicrographs at ×20 magnification; (2) size of nuclei: the short diameter of the nuclei was measured as for the cardiomyocytes; (3) shape of nuclei: shape index (SI) was calculated by the method of Nerem et al 11 according to the following formula: SI = (4 × area/perimeter 2 ). The area and perimeter of the nuclei were measured in 75 cells randomly selected from 5 photomicrographs at ×20 magnification; (4) proportion of fibrosis (F%): Adobe Photoshop software version 6.0 (Adobe Systems Inc) was used to identify red and green in the elastica-Masson Goldner stained specimens, and the ratio of myocardium to fibrotic area was calculated using the following formula: 12 F% = (area of fibrosis/area of fibrosis and myocardium) ×100.…”

Section: Morphometrymentioning

confidence: 99%

Histopathological Features of the Resected Left Atrial Appendage as Predictors of Recurrence After Surgery for Atrial Fibrillation in Valvular Heart Disease

Saito

Tamura

Uchida

et al. 2007

Circ J

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Background A histopathological assessment of left atrial appendages (LAA) resected during surgical treatment for atrial fibrillation (AF) was made, with the aim of improving the prediction of postoperative AF recurrence. Methods and ResultsThis clinicopathological study involved 57 surgical cases of valvular AF and 34 ageand sex-matched control autopsy cases with a history of sinus rhythm. LAA from the cases with valvular AF showed greater hypertrophy of cardiomyocytes (p<0.0001), greater nuclear enlargement (p<0.0001), more bizarre nuclei (BN; p<0.0001), and more intercellular fibrosis (ICF; p<0.001). Partial disarray of cardiomyocytes and fatty infiltration were recognized in both the AF and control groups. Thirty-seven cases had maintained sinus rhythm after surgery from 7 months to 10 years. AF recurred within a month of surgery in 17 and after a month in 3; there was no significant difference in histopathological features between them. These 20 cases had more cellular hypertrophy (p<0.025), nuclear enlargement (p<0.025), BN (p<0.01), and ICF (p<0.025) than those who maintained sinus rhythm after surgery. Conclusions The histopathological findings for LAA reflected the underlying valvular diseases; however, the most reliable predictors of postoperative AF recurrence were hypertrophy of cardiomyocytes, bizarre shaped nuclei, and extensive ICF. (Circ J 2007; 71: 70 -78)

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Vascular Endothelial Morphology as an Indicator of the Pattern of Blood Flow

Cited by 285 publications

References 0 publications

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Finite-Element Stress Analysis of a Multicomponent Model of Sheared and Focally-Adhered Endothelial Cells

Histopathological Features of the Resected Left Atrial Appendage as Predictors of Recurrence After Surgery for Atrial Fibrillation in Valvular Heart Disease

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