Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo

Yamamoto, Kota; Protack, Clinton D.; Kuwahara, Go; Hashimoto, Takeji; Hall, Michael R.; Assi, Roland; Brownson, Kirstyn E.; Foster, Trenton R.; Bai, Hualong; Wang, Mo; Madri, Joseph A.; Dardik, Alan

doi:10.14814/phy2.12348

Cited by 24 publications

(15 citation statements)

References 45 publications

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“…In ECs exposed to unidirectional flow, we observed, as expected, cell alignment and actin fiber orientation with flow direction, while in those exposed to reciprocating flow EC shape remained cuboidal with only peripheral cytoskeletal organization. In line with previous investigations by other groups (26, 27), we confirmed significant expression of KLF-2 in ECs exposed to unidirectional pulsatile flow, while cell exposure to reciprocating flow did not induce KLF-2 expression. Of interest, in ECs exposed to unstable and reciprocating flow we observed an increase in MCP-1 and IL-8 expression (24).…”

Section: The Presence Of Disturbed Flow Patterns In Avfsupporting

confidence: 93%

Is shear stress the key factor for AVF maturation?

2017

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Autologous arteriovenous fistula (AVF) is the preferred choice for providing vascular access to hemodialysis (HD) patients, but it is still affected by high incidence of non-maturation or early failure. After creation, AVF must undergo vascular remodeling, a process characterized by an increase in blood vessel diameter and wall thickness, to allow efficient and adequate HD. A growing body of evidence indicates that AVF maturation is related to the response of endothelial cells (ECs) to changes in wall shear stress (WSS), and in particular, to changes of its peak value. The reasons why important number of AVFs are affected by non-maturation or early failure still remain to be elucidated, but it has been suggested that local hemodynamic conditions with highly disturbed flow patterns may play an important role. In the present contribution, we addressed the role of WSS on AVF maturation, clarifying mechanisms that affect the clinical outcome of AVF creation. We also pointed out the need of non-invasive longitudinal studies, with repeated observations of hemodynamic parameters and structural changes during time, to obtain evidence of a cause-and-effect relationship between the presence of disturbed flow and AVF maturation failure. This understanding may be fundamental in the future to ameliorate clinical outcome of AVF creation, with a great impact on the clinical management of HD patients and their quality of life.

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Section: The Presence Of Disturbed Flow Patterns In Avfsupporting

confidence: 93%

Is shear stress the key factor for AVF maturation?

2017

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“…In line with other investigations available in literature (13,18,72,78), our present results confirmed that EC expression of mRNA coding for KLF2 was significantly increased by cell exposure to UND WSS. At the same time, this flow condition induced a decrease in the mRNA expression of PLD1, ITGA4, and RASA1.…”

Section: H55supporting

confidence: 93%

Endothelial cell activation by hemodynamic shear stress derived from arteriovenous fistula for hemodialysis access

Franzoni

Cattaneo

Longaretti

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Intimal hyperplasia (IH) is the first cause of failure of an arteriovenous fistula (AVF). The aim of the present study was to investigate the effects on endothelial cells (ECs) of shear stress waveforms derived from AVF areas prone to develop IH. We used a cone-and-plate device to obtain real-time control of shear stress acting on EC cultures. We exposed human umbilical vein ECs for 48 h to different shear stimulations calculated in a side-to-end AVF model. Pulsatile unidirectional flow, representative of low-risk stenosis areas, induced alignment of ECs and actin fiber orientation with flow. Shear stress patterns of reciprocating flow, derived from high-risk stenosis areas, did not affect EC shape or cytoskeleton organization, which remained similar to static cultures. We also evaluated flow-induced EC expression of genes known to be involved in cytoskeletal remodeling and expression of cell adhesion molecules. Unidirectional flow induced a significant increase in Kruppel-like factor 2 mRNA expression, whereas it significantly reduced phospholipase D1, α4-integrin, and Ras p21 protein activator 1 mRNA expression. Reciprocating flow did not increase Kruppel-like factor 2 mRNA expression compared with static controls but significantly increased mRNA expression of phospholipase D1, α4-integrin, and Ras p21 protein activator 1. Reciprocating flow selectively increased monocyte chemoattractant protein-1 and IL-8 production. Furthermore, culture medium conditioned by ECs exposed to reciprocating flows selectively increased smooth muscle cell proliferation compared with unidirectional flow. Our results indicate that protective vascular effects induced in ECs by unidirectional pulsatile flow are not induced by reciprocating shear forces, suggesting a mechanism by which oscillating flow conditions may induce the development of IH in AVF and vascular access dysfunction.

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“…In the vascular endothelium, KLF2 has been widely studied; it is upregulated in high laminar unidirectional shear stress (physiological conditions) and downregulated in low oscillatory shear stress (pathophysiological conditions) (35,128,137). In extensive in vitro experiments, human aortic valve endothelial cells (HAVECs) from noncalcified aortic valves exhibited higher KLF2 expression in high unidirectional shear stress (20 dynes/cm 2 , conditions similar to ventricularis) and lower expression in low and oscillatory shear stress (-5 dynes/cm 2 , conditions similar to fibrosa), reflecting the fact that the ventricularis side shows higher KLF2 expression and an antiinflammatory phenotype (50).…”

Section: Kruppel-like Factorsmentioning

confidence: 99%

Shear-Sensitive Genes in Aortic Valve Endothelium

Esmerats

Heath

2016

Antioxidants & Redox Signaling

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Significance: Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction. Recent Advances: While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms-proteins, sugars, and membrane structures-at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-b signaling and Wnt/b-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD. Critical Issues: While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease. Future Directions: Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401-414.

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Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo

Cited by 24 publications

References 45 publications

Is shear stress the key factor for AVF maturation?

Is shear stress the key factor for AVF maturation?

Endothelial cell activation by hemodynamic shear stress derived from arteriovenous fistula for hemodialysis access

Shear-Sensitive Genes in Aortic Valve Endothelium

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