Endothelial Gene Regulation by Laminar Shear Stress

Resnick, Nitzan; Yahav, Hava; Khachigian, Levon M.; Collins, Tucker; Anderson, Keith R.; Dewey, Forbes C.; Gimbrone, Michael A.

doi:10.1007/978-1-4615-5959-7_13

Cited by 103 publications

(54 citation statements)

References 16 publications

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“…In addition, cultures exposed to physiologically low rates of flow yield gene expression profiles similar to endothelium from atherosclerotic-prone arteries (e.g. carotid bifurcations) (Dardik, 2005;Brooks et al, 2004;Resnick, 1997;Wasserman and Topper, 2004) and also show higher levels of endothelial apoptosis (Tricot, 2000). In the present study a model is proposed for a unique vascular structure, in which there is a circulatory input (visualised by 150 kDa FITC-dextran) but very low flow and therefore the shear stress is also low.…”

Section: Discussionmentioning

confidence: 85%

Experimental and theoretical modelling of blind-ended vessels within a developing angiogenic plexus

Guerreiro-Lucas

Pop

Machado

et al. 2008

Microvascular Research

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Angiogenic sprouts at the leading edge of an expanding vascular plexus are recognised as major regulators of the structure of the developing network. Early in sprout development, a vascular lumen is often evident which communicates with the parent vessel while the distal tip is blind-ended. Here we describe the temporal evolution of blind-ended vessels (BEVs) in a small wound made in the panniculus carnosus muscle of a mouse viewed in a dorsal skin-fold window-chamber model with intra-vital microscopy during the most active period of angiogenesis (days 5-8 after injury). Although these structures have been mentioned anecdotally in previous studies, we observed BEVs to be frequent, albeit transient, features of plexus formation. Plasma leakage into the surrounding extracellular matrix occurring from these immature conduits could play an important role in preparing hypoxic tissue for vascular invasion. Although sprout growth is likely to be regulated by its flow environment, the parameters regulating flow into and through BEVs have not been characterised in situ. Longitudinal data from individual animals show that the number of BEVs filled with plasma alone peaks at day 7, when they can exceed 150 μm in length. Additionally, BEVs greater than 40 μm in length are more likely to be filled with stationary erythrocytes than with plasma alone. Using a mathematical model, we show how the flux of 150kD fluorinated (FITC-) dextran through an individual plasma-filled BEV is related to its geometry being determined primarily by its surface area; by fitting theoretical intensity values to experimental data we assess the permeability of the vessel to FITC-dextran. Plasma skimming provides a mechanistic explanation for the observation that BEVs with larger surface area are more likely to recruit erythrocytes.

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Section: Discussionmentioning

confidence: 85%

Experimental and theoretical modelling of blind-ended vessels within a developing angiogenic plexus

Guerreiro-Lucas

Pop

Machado

et al. 2008

Microvascular Research

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“…However, the deletion and mutation of these elements had no effect on the fluid shear stress-induced increase in luciferase activity, suggesting that these sites are not associated with the shear stress-activated COX-2 transcription. In addition, the COX-2 promoter region also contains a sequence (GAGACC, Ϫ305 to Ϫ300 bp) of shear stress response element (SSRE), which was initially reported in the promoter of the PDGF-B gene (57). However, the deletion of the COX-2 promoter region from Ϫ366 to Ϫ172 bp including the SSRE site failed to decrease the shear stress-induced luciferase response, implying the independence of the response from SSRE.…”

Section: Figmentioning

confidence: 98%

Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP β, cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells

Ogasawara

Arakawa

Kaneda

et al. 2001

Journal of Biological Chemistry

145

104

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Mechanical loading is crucial for maintenance of bone integrity and architecture, and prostaglandins are an important mediator of mechanosensing. Cyclooxygenase-2 (COX-2), an inducible isoform of prostaglandin G/H synthase, is induced by mechanical loading-derived fluid shear stress in bone-forming cells such as osteoblasts and osteocytes. In this study, we investigated transcription factor and transcriptional regulatory elements responsible for the shear stress-induced COX-2 expression in osteoblastic MC3T3-E1 cells. When the cells were transfected with luciferase-reporter plasmids including the 5-flanking region of the murine cox-2 gene, the fluid shear stress increased the luciferase activities, consistent with the induction of COX-2 mRNA and protein expression. Deletion analysis of the promoter region revealed that the shear stress-induced luciferase responses were regulated by two regions, ؊172 to ؊100 base pair (bp) and ؊79 to ؊46 bp, of the cox-2 promoter, in which putative cis-elements of C/EBP ␤, AP-1, cAMP-response element-binding protein (CREB), and E box are included. Mutation of sites of C/EBP ␤, AP-1, and/or cAMP-response element decreased the shear stress-induced luciferase activities, whereas mutation of the E box did not affect the responses. In an electrophoretic mobility shift assay, shear stress enhanced nuclear extract binding to double-stranded oligonucleotide probes containing C/EBP ␤ and AP-1-binding motifs, and the bands of the complexes were supershifted by the addition of antibody specific for each regulator. Although the binding activity of CREB toward its probe was unaffected by shear stress, the phosphorylation of CREB was enhanced by the stress. These data suggest that C/EBP ␤, AP-1, and CREB play crucial roles in the shear stress-induced cox-2 expression in osteoblasts.Mechanical loading applied to the skeleton is crucial to the development and maintenance of bone integrity and architecture. A decrease in the mechanical loading due to prolonged immobilization or weightlessness in space reduces the bone formation rate, resulting in bone loss (1-3). On the other hand, an increase in mechanical loading causes a gain in bone density (4, 5). Thus, bone tissue is sensitive to mechanical stimulation. Mechanical loading on bone generates extracellular matrix deformation and fluid flow, and the mechanical stimuli are translated to mechanical signals such as mechanical strain and fluid shear stress, respectively (6). Evidence obtained from in vitro studies indicates that osteocytes embedded in the lacunae/ canaliculi system and osteoblasts and bone cells lining the bone surface are mechanosensors that detect load-derived mechanical stimuli (7,8). By these bone-forming cells, the mechanical stimuli are translated into cellular signaling factors.Mechanical stress induces the expressions of several kinds of proteins in bone-forming cells such as insulin-like growth factor-I and -II, transforming growth factor-␤, osteocalcin, osteopontin, c-Fos, nitric-oxide synthase, and cyclooxygenase-2 (COX-...

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“…Importantly, the migration of monocytes is fundamentally associated with angiogenesis and arteriogenesis in the ischemic environment [50,51]. Monocytes are recruited in response to hypoxia, migrate along defined chemotactic gradients, and accumulate within the hypoxic regions of ischemia [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

The Role of CCL5 in the Ability of Adipose Tissue-Derived Mesenchymal Stem Cells to Support Repair of Ischemic Regions

Kimura

Nagano

Salazar

et al. 2014

Stem Cells and Development

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Mesenchymal stem cells (MSC) are multipotent and possess high proliferative activity, and thus are thought to be a reliable cell source for cell therapies. Here, we isolated MSC from adult tissues-bone marrow (BM-MSC), dental tissue (DT-MSC), and adipose tissue (AT-MSC)-to compare how autotransplantation of these MSC effectively supports the repair of bone fracture and ischemic tissue. An analysis by in vitro differentiation assays showed no significant difference among these MSC. The degree of calcification at the joint region of bone fracture was higher in mice transplanted with AT-MSC than in mice transplanted with BM-MSC or DT-MSC. To compare the abilities of MSC, characterize how those MSC affect the repair of ischemic tissue, vascular occlusion was performed by ligation of the femoral artery and vein. Of note, the blood flow in the ischemic region rapidly increased in mice injected with AT-MSC, as contrasted with mice injected with BM-or DT-MSC. The number of CD45-and F4/80-positive cells at the femoral region was higher in AT-MSC recipients than in recipients of BM-MSC or DT-MSC. We evaluated the mRNA expression of angiogenic and migration factors in MSC and found the expression of CCL5 mRNA was higher in AT-MSC than in BM-MSC or DT-MSC. Transplantation of AT-MSC with impaired expression of CCL5 clearly showed a significant delay in the recovery of blood flow compared with the control. These findings have fundamental implications for the modulation of AT-MSC in the repair of vasculature and bone fracture.

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Endothelial Gene Regulation by Laminar Shear Stress

Cited by 103 publications

References 16 publications

Experimental and theoretical modelling of blind-ended vessels within a developing angiogenic plexus

Experimental and theoretical modelling of blind-ended vessels within a developing angiogenic plexus

Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP β, cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells

The Role of CCL5 in the Ability of Adipose Tissue-Derived Mesenchymal Stem Cells to Support Repair of Ischemic Regions

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