Flow shear stress controls the initiation of neovascularization via heparan sulfate proteoglycans within a biomimetic microfluidic model

The role of shear stress was investigated in a biomimetic microfluidic model that recapitulates the initial physiological microenvironment of neovascularization.

Role of the cytoskeleton in flow (shear stress)-induced dilation and remodeling in resistance arteries

Medical & Biological Engineering & Computing ◽

10.1007/s11517-008-0306-2 ◽

2008 ◽

Vol 46 (5) ◽

pp. 451-460 ◽

Cited By ~ 39

Author(s):

Laurent Loufrani ◽

Daniel Henrion

Keyword(s):

Shear Stress ◽

Resistance Arteries ◽

Flow Shear ◽

Key role of α1β1-integrin in the activation of PI3-kinase-Akt by flow (shear stress) in resistance arteries

10.1152/ajpheart.00966.2006 ◽

2008 ◽

Vol 294 (4) ◽

pp. H1906-H1913 ◽

Cited By ~ 28

Author(s):

Laurent Loufrani ◽

Kevin Retailleau ◽

Arnaud Bocquet ◽

Odile Dumont ◽

Kerstin Danker ◽

...

Keyword(s):

Shear Stress ◽

Metabolic Diseases ◽

Inhibitory Effect ◽

Pi3 Kinase ◽

Resistance Arteries ◽

Flow Shear ◽

Phosphorylated Akt ◽

Flow Shear Stress ◽

Stress Dependent

Resistance arteries are the site of the earliest manifestations of many cardiovascular and metabolic diseases. Flow (shear stress) is the main physiological stimulus for the endothelium through the activation of vasodilatory pathways generating flow-mediated dilation (FMD). The role of FMD in local blood flow control and angiogenesis is well established, and alterations in FMD are early markers of cardiovascular disorders. α1-Integrin, which has a role in angiogenesis, could be involved in FMD. FMD was studied in mesenteric resistance arteries (MRA) isolated in arteriographs. The role of α1-integrins in FMD was tested with selective antibodies and mice lacking the gene encoding for α1-integrins. Both anti-α1blocking antibodies and genetic deficiency in α1-integrin in mice (α1−/−) inhibited FMD without affecting receptor-mediated (acetylcholine) endothelium-dependent dilation or endothelium-independent dilation (sodium nitroprusside). Similarly, vasoconstrictor tone (myogenic tone and phenylephrine-induced contraction) was not affected. In MRA phosphorylated Akt and phosphatidylinositol 3-kinase (PI3-kinase) were significantly lower in α1−/−mice than in α1+/+mice, although total Akt and endothelial nitric oxide synthase (eNOS) were not affected. Pharmacological blockade of PI3-kinase-Akt pathway with LY-294002 inhibited FMD. This inhibitory effect of LY-294002 was significantly lower in α1−/−mice than in α1+/+mice. Thus α1-integrin has a key role in flow (shear stress)-dependent vasodilation in resistance arteries by transmitting the signal to eNOS through activation of PI3-kinase and Akt. Because of the central role of flow (shear stress) activation of the endothelium in vascular disorders, this finding opens new perspectives in the pathophysiology of the microcirculation and provides new therapeutic targets.

A test of the role of flow-dependent dilation in arteriolar responses to occlusion

10.1152/ajpheart.1997.272.2.h714 ◽

1997 ◽

Vol 272 (2) ◽

pp. H714-H721 ◽

Cited By ~ 12

Author(s):

E. D. McGahren ◽

K. A. Dora ◽

D. N. Damon ◽

B. R. Duling

Keyword(s):

Shear Stress ◽

Baseline Level ◽

Cheek Pouch ◽

Hamster Cheek Pouch ◽

Flow Shear ◽

Flow Through ◽

Flow Shear Stress ◽

Arteriolar Diameter

At an arteriolar bifurcation, occlusion of one of the branch arterioles has been reported to result in an increase in flow, shear stress, and vasodilation in the opposite unoccluded branch. This dilator response in the unoccluded branch, often referred to as the "parallel occlusion response," has been cited as evidence that flow-dependent dilation is a primary regulator of arteriolar diameter in the microcirculation. It has not been previously noted that, during this maneuver, flow through the feed arteriole would be expected to decrease and logically should cause that vessel to constrict. We tested this prediction in vivo by measuring red blood cell (RBC) velocity and diameter changes in response to arteriolar occlusion in the microcirculatory beds of three preparations: the hamster cheek pouch, the hamster cremaster, and the rat cremaster. In all preparations, a vasodilation was observed in the feed arteriole, despite a decrease in both flow and calculated wall shear stress through this vessel. Unexpectedly, we found that dilation occurred in the unoccluded branch arterioles even in those cases in which RBC velocity and shear stress did not increase in the unoccluded branch arterioles. All values returned to the baseline level after the removal of occlusion. The magnitude of the dilation of the feed and branch arterioles varied between species and tissues, but feed and branch arterioles within a given preparation always responded in a similar way to each other. We conclude from our experiments that mechanisms other than flow-dependent dilation are involved in the vasodilation observed in the microcirculation during occlusion of an arteriolar branch.

Volume 1B: Extremity; Fluid Mechanics; Gait; Growth, Remodeling, and Repair; Heart Valves; Injury Biomechanics; Mechanotransduction and Sub-Cellular Biophysics; MultiScale Biotransport; Muscle, Tendon and Ligament; Musculoskeletal Devices; Multiscale Mechanics; Thermal Medicine; Ocular Biomechanics; Pediatric Hemodynamics; Pericellular Phenomena; Tissue Mechanics; Biotransport Design and Devices; Spine; Stent Device Hemodynamics; Vascular Solid Mechanics; Student Paper and Design Competitions ◽

Tissue Engineered Tumor Microvessels to Study the Role of Flow Shear Stress on Endothelial Barrier Function

10.1115/sbc2013-14592 ◽

2013 ◽

Author(s):

Cara F. Buchanan ◽

Elizabeth Voigt ◽

Pavlos P. Vlachos ◽

Marissa Nichole Rylander

Keyword(s):

Shear Stress ◽

Growth Factors ◽

Vascular Function ◽

Fluid Pressure ◽

Compressive Force ◽

Lymphatic Drainage ◽

Angiogenic Growth Factors ◽

Flow Shear ◽

As solid tumors develop, a variety of physical stresses arise including growth induced compressive force, matrix stiffening due to desmoplasia, and increased interstitial fluid pressure and altered flow patterns due to leaky vasculature and poor lymphatic drainage [1]. These microenvironmental stresses likely contribute to the abnormal cell behavior that drives tumor progression, and have become an increasingly significant area of cancer research. Of particular importance, is the role of flow shear stress on tumor-endothelial signaling, vascular function, and angiogenesis. Compared to normal vasculature, blood vessels in tumors are poorly functional due to dysregulated expression of angiogenic growth factors, such as vascular endothelial growth factor (VEGF) or the angiopoietins. Also, because of the abnormal vessel structure, blood velocities can be an order of magnitude lower than that of normal microvessels. Recently published work utilizing intravital microscopy to measure blood velocities in mouse mammary fat pad tumors, demonstrated for the first time that shear rate gradients in tumors may help guide branching and growth of new vessels [2]. However, much still remains unknown about how shear stress regulates endothelial organization, permeability, or expression of growth factors within the context of the tumor microenvironment.

I022 Role of heme oxygenase-1 in high blood flow (shear stress)-induced remodeling of rat resistance arteries

Archives of Cardiovascular Diseases ◽

10.1016/s1875-2136(09)72356-3 ◽

2009 ◽

Vol 102 ◽

pp. S94

Author(s):

M.-L. Freidja ◽

E. Vessieres ◽

B. Toutain ◽

L. Loufrani ◽

S. Faure ◽

...

Keyword(s):

Blood Flow ◽

Shear Stress ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Resistance Arteries ◽

Flow Shear ◽

Letters to the Editor

10.1152/ajpheart.1998.274.1.h382 ◽

1998 ◽

Vol 274 (1) ◽

pp. H382-H383 ◽

Cited By ~ 2

Author(s):

Akos Koller gabor Kaley

Keyword(s):

Shear Stress ◽

Cheek Pouch ◽

Hamster Cheek Pouch ◽

Letters To The Editor ◽

Flow Shear ◽

Flow Through ◽

Flow Shear Stress ◽

Arteriolar Diameter

The following is the abstract of the article discussed in the subsequent letter: McGahren, Eugene D., Kim A. Dora, David N. Damon, and Brian R. Duling. A test of the role of flow-dependent dilation in arteriolar responses to occlusion. Am. J. Physiol. 272 ( Heart Circ. Physiol. 41): H714–H721, 1997.—At an arteriolar bifurcation, occlusion of one of the branch arterioles has been reported to result in an increase in flow, shear stress, and vasodilation in the opposite unoccluded branch. This dilator response in the unoccluded branch, often referred to as the “parallel occlusion response,” has been cited as evidence that flow-dependent dilation is a primary regulator of arteriolar diameter in the microcirculation. It has not been previously noted that, during this maneuver, flow through the feed arteriole would be expected to decrease and logically should cause that vessel to constrict. We tested this prediction in vivo by measuring red blood cell (RBC) velocity and diameter changes in response to arteriolar occlusion in the microcirculatory beds of three preparations: the hamster cheek pouch, the hamster cremaster, and the rat cremaster. In all preparations, a vasodilation was observed in the feed arteriole, despite a decrease in both flow and calculated wall shear stress through this vessel. Unexpectedly, we found that dilation occurred in the unoccluded branch arterioles even in those cases in which RBC velocity and shear stress did not increase in the unoccluded branch arterioles. All values returned to the baseline level after the removal of occlusion. The magnitude of the dilation of the feed and branch arterioles varied between species and tissues, but feed and branch arterioles within a given preparation always responded in a similar way to each other. We conclude from our experiments that mechanisms other than flow-dependent dilation are involved in the vasodilation observed in the microcirculation during occlusion of an arteriolar branch.

Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)82186-x ◽

1993 ◽

Vol 268 (14) ◽

pp. 10160-10167

Author(s):

Z.S. Ji ◽

W.J. Brecht ◽

R.D. Miranda ◽

M.M. Hussain ◽

T.L. Innerarity ◽

...

Keyword(s):

Apolipoprotein E ◽

Heparan Sulfate ◽

Cultured Cells ◽

Heparan Sulfate Proteoglycans ◽

Remnant Lipoproteins

The Effect of Fluid Flow Shear Stress and Substrate Stiffness on Yes-Associated Protein (YAP) Activity and Osteogenesis in Murine Osteosarcoma Cells

Cancers ◽

10.3390/cancers13133128 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3128

Author(s):

Thomas R. Coughlin ◽

Ali Sana ◽

Kevin Voss ◽

Abhilash Gadi ◽

Upal Basu-Roy ◽

...

Keyword(s):

Shear Stress ◽

Fluid Flow ◽

Bone Cells ◽

Bone Cancer ◽

Substrate Stiffness ◽

Flow Shear ◽

Fluid Movement ◽

Flow Shear Stress ◽

Fluid Flow Shear Stress ◽

New Treatments

Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness—two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity—which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression.

Temporal gradient in shear-induced signaling pathway: involvement of MAP kinase, c-fos, and connexin43

10.1152/ajpheart.2000.278.5.h1598 ◽

2000 ◽

Vol 278 (5) ◽

pp. H1598-H1605 ◽

Cited By ~ 68

Author(s):

Xuping Bao ◽

Craig B. Clark ◽

John A. Frangos

Keyword(s):

Shear Stress ◽

Mrna Expression ◽

Signaling Pathway ◽

Steady Shear ◽

Flow Shear ◽

Temporal Gradient ◽

Step Flow ◽

Shear Component ◽

Flow Shear Stress ◽

Impulse Flow

The effect of a temporal gradient in shear and steady shear on the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/ERK2), c- fos, and connexin43 (Cx43) in human endothelial cells was investigated. Three laminar flow profiles (16 dyn/cm2), including impulse flow (shear stress abruptly applied for 3 s), ramp flow (shear stress smoothly transitioned at flow onset), and step flow (shear stress abruptly applied at flow onset) were utilized. Relative to static controls, impulse flow stimulated the phosphorylation of ERK1/ERK2 8.5- to 7.5-fold, respectively at 10 min, as well as the mRNA expression of c- fos 51-fold at 30 min, and Cx43 8-fold at 90 min. These high levels of mRNA expression were sustained for at least 4 h. In contrast, ramp flow was unable to significantly induce gene expression and even inhibited the activation of ERK1/ERK2. Step flow, which contains both a sharp temporal gradient in shear stress and a steady shear component, elicited only moderate and transient responses, indicating the distinct role of these fluid shear stimuli in endothelial signal transduction. The specific inhibitor of mitogen-activated protein kinase kinase PD-98059 inhibited impulse flow-induced c -fos and Cx43 mRNA expression. Thus these findings implicate the involvement of ERK1/ERK2, c -fos, and Cx43 in the signaling pathway induced by the temporal gradient in shear.