Laminar flow downregulates Notch activity to promote lymphatic sprouting

Choi, Dongwon; Park, Eunkyung; Jung, Eunson; Seong, Young Jin; Yoo, Jae Gyu; Lee, Esak; Hong, Mingu; Lee, Sun-Ju; Ishida, Hiroaki; Burford, James; Peti‐Peterdi, Janos; Adams, Ralf H.; Srikanth, Sonal; Gwack, Yousang; Chen, Christopher; Vogel, Hans J.; Koh, Chester J.; Wong, Alex K.; Hong, Young Kwon

doi:10.1172/jci87442

Cited by 117 publications

(127 citation statements)

References 63 publications

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“…In a previous microfluidic study, it was shown that LSS (3 dyn/cm 2 ) suppressed VEGF‐A induced blood vessel sprouting . Therefore, the results reported by Choi et al provide a molecular basis for the divergent shear stress‐mediated responses by LECs and BECs as it pertains to lymphangiogenesis and angiogenesis. Finally, a recent study by Kamm and colleagues developed a dual cylindrical vessel model to form fully perfusable and parallel lymphatic and blood microvessels .…”

Section: Microfluidic Approaches For Studying Lymphatic Vasculaturementioning

confidence: 82%

“…In a separate study, Chung et al created a biomimetic TME model that allowed for simultaneous observation of angiogenesis and lymphangiogenesis while co‐cultured with cancer cells and fibroblasts. Choi et al used a cylindrical 3‐D vessel assay that demonstrated that LSS (2 dyn/cm 2 ) selectively suppresses Notch activation in LECs but not BECs, resulting in an increase in lymphatic sprouting. In a previous microfluidic study, it was shown that LSS (3 dyn/cm 2 ) suppressed VEGF‐A induced blood vessel sprouting .…”

Section: Microfluidic Approaches For Studying Lymphatic Vasculaturementioning

confidence: 99%

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Application of microscale culture technologies for studying lymphatic vessel biology

2019

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Immense progress in microscale engineering technologies has significantly expanded the capabilities of in vitro cell culture systems for reconstituting physiological microenvironments that are mediated by biomolecular gradients, fluid transport, and mechanical forces. Here, we examine the innovative approaches based on microfabricated vessels for studying lymphatic biology. To help understand the necessary design requirements for microfluidic models, we first summarize lymphatic vessel structure and function. Next, we provide an overview of the molecular and biomechanical mediators of lymphatic vessel function. Then we discuss the past achievements and new opportunities for microfluidic culture models to a broad range of applications pertaining to lymphatic vessel physiology. We emphasize the unique attributes of microfluidic systems that enable the recapitulation of multiple physicochemical cues in vitro for studying lymphatic pathophysiology. Current challenges and future outlooks of microscale technology for studying lymphatics are also discussed. Collectively, we make the assertion that further progress in the development of microscale models will continue to enrich our mechanistic understanding of lymphatic biology and physiology to help realize the promise of the lymphatic vasculature as a therapeutic target for a broad spectrum of diseases.

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Section: Microfluidic Approaches For Studying Lymphatic Vasculaturementioning

confidence: 82%

Section: Microfluidic Approaches For Studying Lymphatic Vasculaturementioning

confidence: 99%

Application of microscale culture technologies for studying lymphatic vessel biology

2019

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“…A novel aspect of lymphatic vascular biology is the role of integrins and mechanical forces in VEGFR3 signalling, lymphatic vascular growth and valve morphogenesis (Wang et al , ; Bazigou et al , ; Galvagni et al , ; Planas‐Paz et al , ; Baeyens et al , ; Sweet et al , ; Sabine et al , ; Choi et al , ). Integrins are transmembrane receptors, which bind to extracellular matrix (ECM) components, and are essential for “outside‐in” and “inside‐out” signalling of the cell, thereby transducing mechanical stimulations.…”

Section: Introductionmentioning

confidence: 99%

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

et al. 2018

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Vascular endothelial growth factor receptor‐3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell‐specific depletion of integrin‐linked kinase (ILK) in mouse embryos hyper‐activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)‐specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and β1 integrin in vitro and in vivo, and endothelial cell‐specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and β1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with β1 integrin and thus ensures proper development of lymphatic vessels.

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“…We exposed HLECs to 5 dynes/cm 2 LSS as described by Choi et al (18,19) and investigated whether S1PR1 and LSS could synergize in restricting the expression of tip cell markers. Indeed, LSS potently inhibited the expression of DLL4, ANGPT2, ESM1 and ADM in both control siRNA and siS1PR1-treated HLECs (Figure 3C).…”

Section: Laminar Shear Stress (Lss) Inhibits the Expression Of Tip-cementioning

confidence: 99%

S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling

Geng

Yanagida

Akwii

et al. 2020

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During the growth of lymphatic vessels (lymphangiogenesis), lymphatic endothelial cells (LECs) at the growing front sprout by forming filopodia. Those tip cells are not exposed to circulating lymph, as they are not lumenized. In contrast, LECs that trail the growing front are exposed to shear stress, become quiescent and remodel into stable vessels. The mechanisms that coordinate the opposed activities of lymphatic sprouting and maturation remain poorly understood. Here we show that the canonical tip cell marker Delta-Like 4 (DLL4) promotes sprouting lymphangiogenesis by enhancing Vascular Endothelial Growth Factor C (VEGF-C) /VEGF Receptor 3 (VEGFR3) signaling. However, in lumenized lymphatic vessels laminar shear stress (LSS) inhibits the expression of DLL4, as well as additional tip cell markers.Paradoxically, LSS also upregulates VEGF-C/VEGFR3 signaling in LECs, but sphingosine 1phosphate (S1P) receptor 1 (S1PR1) activity antagonizes LSS-mediated VEGF-C signaling to promote lymphatic vascular quiescence. Correspondingly, S1pr1 loss in LECs induced lymphatic vascular hypersprouting and hyperbranching, which could be rescued by reducing Vegfr3 gene dosage in vivo. In addition, S1PR1 regulates lymphatic vessel maturation by promoting membrane localization of the tight junction molecule Claudin-5. Our findings suggest a new paradigm in which LSS induces quiescence and promotes the survival of LECs by downregulating DLL4 and enhancing VEGF-C signaling, respectively. S1PR1 dampens LSS/VEGF-C signaling, thereby preventing sprouting from quiescent lymphatic vessels.

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Laminar flow downregulates Notch activity to promote lymphatic sprouting

Cited by 117 publications

References 63 publications

Application of microscale culture technologies for studying lymphatic vessel biology

Application of microscale culture technologies for studying lymphatic vessel biology

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling

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