Oscillatory shear potentiates latent TGF-β1 activation more than steady shear as demonstrated by a novel force generator

Kouzbari, Karim; Hossan, Mohammad Robiul; Arrizabalaga, Julien H.; Varshney, Rohan; Simmons, Aaron D.; Gostynska, Sandra; Nollert, Matthias U.; Ahamed, Jasimuddin

doi:10.1038/s41598-019-42302-x

Cited by 28 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the mechanosensitive mechanisms controlling TGFβ family signaling is integrin‐dependent activation of latent TGFβ ligand 52 . While FSS has been shown to activate latent TGFβ through a mechanism sensitive to FSS magnitude and flow profile (steady vs oscillatory 17 ), we find that FSS stimulates Smad phosphorylation even with saturating levels of active TGFβ ligand. This suggests that mechanoactivation of latent TGFβ is not the sole mechanism through which FSS targets this pathway in osteocytes.…”

Section: Discussionmentioning

confidence: 59%

“…Kunnen et al report that FSS‐mediated activation of TGFβ signaling is blocked in cells treated with the ALK4/5/7 inhibitor LY‐364947, and also observed mild decreases of active and total TGFβ1 levels in flow media following application of FSS 16 . On the contrary, Kouzbari et al and Albro et al showed that levels of active TGFβ1 in platelet releasates and synovial fluid, respectively, increase after stimulation with FSS 17,18 . As a result, the extent to which this mechanism depends primarily on ligand‐level, receptor‐level, or downstream regulation in a cell type‐specific manner remains unclear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fluid shear stress generates a unique signaling response by activating multiple TGFβ family type I receptors in osteocytes

et al. 2021

View full text Add to dashboard Cite

Bone is a dynamic tissue that constantly adapts to changing mechanical demands. The transforming growth factor beta (TGFβ) signaling pathway plays several important roles in maintaining skeletal homeostasis by both coupling the bone‐forming and bone‐resorbing activities of osteoblasts and osteoclasts and by playing a causal role in the anabolic response of bone to applied loads. However, the extent to which the TGFβ signaling pathway in osteocytes is directly regulated by fluid shear stress (FSS) is unknown, despite work suggesting that fluid flow along canaliculi is a dominant physical cue sensed by osteocytes following bone compression. To investigate the effects of FSS on TGFβ signaling in osteocytes, we stimulated osteocytic OCY454 cells cultured within a microfluidic platform with FSS. We find that FSS rapidly upregulates Smad2/3 phosphorylation and TGFβ target gene expression, even in the absence of added TGFβ. Indeed, relative to treatment with TGFβ, FSS induced a larger increase in levels of pSmad2/3 and Serpine1 that persisted even in the presence of a TGFβ receptor type I inhibitor. Our results show that FSS stimulation rapidly induces phosphorylation of multiple TGFβ family R‐Smads by stimulating multimerization and concurrently activating several TGFβ and BMP type I receptors, in a manner that requires the activity of the corresponding ligand. While the individual roles of the TGFβ and BMP signaling pathways in bone mechanotransduction remain unclear, these results implicate that FSS activates both pathways to generate a downstream response that differs from that achieved by either ligand alone.

show abstract

Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Fluid shear stress generates a unique signaling response by activating multiple TGFβ family type I receptors in osteocytes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Oscillation of the shear stress on the vascular endothelial cells has been noted in the pathogenesis of vascular dilation through activation of inflammatory signals [ 74 , 92 – 97 ]. Compared with physiological steady shear stress, oscillatory shear stress induces higher activation of TGF-β1 which drives pathological vascular remodelling [ 94 ]. Endothelial cilia dysfunction contributes to aberrant fluid-sensing and thus results in vascular disorders, such as aneurysm formation and atherosclerosis [ 98 , 99 ] Therefore, increased oscillatory shear stress due to reciprocating CSF movements may directly activate flow-mediated dilation at the cerebral aqueduct, and it may generate a synergistic effect of increased stroke volumes at the nearby upstream CSF pathways in the ventricles.…”

Section: Introductionmentioning

confidence: 99%

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia

Yamada

Ishikawa

Nozaki

2021

Fluids Barriers CNS

View full text Add to dashboard Cite

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.

show abstract

“…As cellular functions often depend on cellular shape and orientation, which are determined by flow-induced hemodynamics, effort has been made to model complex blood flow observed in in vivo settings. Atheroprone oscillatory flow can be induced using the cone and plate shear devices [ 40 ] or parallel plate flow chambers [ 41 ]. Sinha et al [ 42 ] have developed a medium-throughput cell culture device that can produce variously oriented anisotropic biaxial strains by stretching a cell-growing surface membrane, which models strains caused by vascular wall changes in shape and mechanical properties, as seen in various vascular diseases, such as atherosclerosis.…”

Section: In Vitro Systems To Model Flow Dynamics and Endothelial Wall Shear Stress (Wss)mentioning

confidence: 99%

Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

Urschel

Tauchi

Achenbach

et al. 2021

IJMS

View full text Add to dashboard Cite

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

show abstract

Oscillatory shear potentiates latent TGF-β1 activation more than steady shear as demonstrated by a novel force generator

Cited by 28 publications

References 29 publications

Fluid shear stress generates a unique signaling response by activating multiple TGFβ family type I receptors in osteocytes

Fluid shear stress generates a unique signaling response by activating multiple TGFβ family type I receptors in osteocytes

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia

Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

Contact Info

Product

Resources

About