Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway

Matsuo, Eisuke; Takayuki, Okamoto; Ito, Atsushi; Kawamoto, Eiji; Asanuma, Kunihiro; Wada, Koichiro; Shimaoka, Motomu; Takao, Motoshi; Shimamoto, Akira

doi:10.1016/j.yexcr.2021.112835

Cited by 10 publications

(9 citation statements)

References 54 publications

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“…The role of the Yes-associated protein YAP as a mechano-transducer and the related mechano-sensitivity of the YAP/TAZ signaling pathway are well known [23, 24]. We and others have shown that YAP activity decreases on soft substrates [25].…”

Section: Resultsmentioning

confidence: 99%

“…1). Endothelial cells sense changes of matrix properties via cell-matrix adhesion proteins, such as integrin β1 [16,33], which also plays a crucial role in regulating cellular adhesion to enable migration and proliferation [23,33]. Since integrins have been previously located both up- [35] and downstream of Notch in signaling pathways [7], we first investigated this issue.…”

Section: Discussionmentioning

confidence: 99%

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Matrix stiffness regulates Notch signaling activity in endothelial cells

Kretschmer

Mamistvalov

Sprinzak

et al. 2022

Preprint

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The Notch signaling pathway plays a critical role in many developmental and disease related processes. It is widely accepted that Notch has a mechano-transduction module that regulates cleavage of the receptor. However, the role of biomechanical properties of the cellular environment on this module and on Notch signaling in general is still poorly understood. During angiogenesis, differentiation into tip and stalk cells is regulated by Notch. The endothelial cells in this process respond to biochemical and mechanical cues triggered by local stiffening of the ECM. Here, we investigated the influence of substrate stiffness on the Notch signaling pathway in endothelial cells. Using stiffness tuned PDMS substrates we show that Notch signaling pathway activity inversely correlates with the physiologically relevant substrate stiffness, with increased Notch activity on softer substrates. We show that trans-endocytosis of the Notch extracellular domain, but not the overall endocytosis, is regulated by substrate stiffness. Furthermore, we could show that integrin cell-matrix connections are both stiffness-dependent and influenced by Notch. Cadherin mediated cell-cell adhesion and Notch, however, influence each other in that basal Notch signaling is cell-cell contact dependent, but inhibition of the Notch signaling pathway also results in a reduction of VE-cadherin levels. We conclude that mechano-transduction of Notch activation depends on substrate stiffness highlighting the role of substrate rigidity as a modulator of Notch signaling. This may have important implications in pathological situations, such as tumor growth, associated with stiffening of the extracellular matrix.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Matrix stiffness regulates Notch signaling activity in endothelial cells

Kretschmer

Mamistvalov

Sprinzak

et al. 2022

Preprint

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“…Furthermore, stiffer blood vessels can have increased permeability and become more likely to develop plaque accumulation, which can lead to further complications ( 82 ). Transcription factors YAP/TAZ, which reside downstream of VEGF/VEGFR-2, are upregulated on stiffer matrices and in disturbed flow, and in vivo inhibition of YAP/TAZ caused decreased atherosclerosis and EC inflammation ( 83 , 84 ). Since many cells are known to respond to environmental mechanical cues, the natural stiffening of arteries could be a contributing factor of further cardiovascular diseases that are more common with age.…”

Section: Angiogenesismentioning

confidence: 99%

“…Since YAP/TAZ are known mechanotransducers, they likely play a role with VEGFR-2 in angiogenic response to mechanical forces. One study demonstrated that HUVECs grown on a 1 kPa matrix caused downregulation of YAP activity and upregulation of VEGFR-2 transcription levels ( 83 ). When VEGF was added, VEGFR-2 levels increased on the 1 kPa gels.…”

Section: Signalingmentioning

confidence: 99%

“…YAP activation by lysophosphatidic acid causes increased delta-like ligand 4 (DLL4) expression, which is a Notch1 ligand ( 230 ). However, in HUVECs, DLL4 showed the highest expression on 1 kPa gels when YAP is least active, and addition of YAP inhibitor verteporfin also caused increased DLL4 expression in HUVECs plated on a stiff 25 kPa gel ( 83 ). Even though previous work has shown that YAP activity can promote DLL4 expression, different combinations of matrix stiffnesses and soluble VEGF leads to varied results, exemplifying how complicated mechanobiology can be.…”

Section: Signalingmentioning

confidence: 99%

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Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

Miller

Sewell-Loftin

2022

Front. Cardiovasc. Med.

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The endothelial cells that compose the vascular system in the body display a wide range of mechanotransductive behaviors and responses to biomechanical stimuli, which act in concert to control overall blood vessel structure and function. Such mechanosensitive activities allow blood vessels to constrict, dilate, grow, or remodel as needed during development as well as normal physiological functions, and the same processes can be dysregulated in various disease states. Mechanotransduction represents cellular responses to mechanical forces, translating such factors into chemical or electrical signals which alter the activation of various cell signaling pathways. Understanding how biomechanical forces drive vascular growth in healthy and diseased tissues could create new therapeutic strategies that would either enhance or halt these processes to assist with treatments of different diseases. In the cardiovascular system, new blood vessel formation from preexisting vasculature, in a process known as angiogenesis, is driven by vascular endothelial growth factor (VEGF) binding to VEGF receptor 2 (VEGFR-2) which promotes blood vessel development. However, physical forces such as shear stress, matrix stiffness, and interstitial flow are also major drivers and effectors of angiogenesis, and new research suggests that mechanical forces may regulate VEGFR-2 phosphorylation. In fact, VEGFR-2 activation has been linked to known mechanobiological agents including ERK/MAPK, c-Src, Rho/ROCK, and YAP/TAZ. In vascular disease states, endothelial cells can be subjected to altered mechanical stimuli which affect the pathways that control angiogenesis. Both normalizing and arresting angiogenesis associated with tumor growth have been strategies for anti-cancer treatments. In the field of regenerative medicine, harnessing biomechanical regulation of angiogenesis could enhance vascularization strategies for treating a variety of cardiovascular diseases, including ischemia or permit development of novel tissue engineering scaffolds. This review will focus on the impact of VEGFR-2 mechanosignaling in endothelial cells (ECs) and its interaction with other mechanotransductive pathways, as well as presenting a discussion on the relationship between VEGFR-2 activation and biomechanical forces in the extracellular matrix (ECM) that can help treat diseases with dysfunctional vascular growth.

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