Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development

Wang, Yingdi; Baeyens, Nicolas; Corti, Federico; Tanaka, Keiichiro; Fang, Jennifer S.; Zhang, Jiasheng; Yu, Jin; Coon, Brian G.; Hirschi, Karen K.; Schwartz, Martin A.; Simons, Michael

doi:10.1242/jcs.200089

Cited by 8 publications

(8 citation statements)

References 12 publications

(14 reference statements)

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“…As expected, ex vivo culture (Sabine et al, 2012(Sabine et al, , 2015. On the other hand, laminar shear stress (LSS) regulates lymphatic vessel remodeling as well as LEC proliferation and quiescence (Wang et al, 2016;Choi et al, 2017aChoi et al, , 2017bGeng et al, 2020 (Sweet et al, 2015). LSS led to a more modest upregulation of FOXP2 (Fig EV3B).…”

Section: Foxp2 Expression Is Regulated By Flowsupporting

confidence: 61%

Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

et al. 2021

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The lymphatic system is composed of a hierarchical network of fluid absorbing lymphatic capillaries and transporting collecting vessels. Despite distinct functions and morphologies, molecular mechanisms that regulate the identity of the different vessel types are poorly understood. Through transcriptional analysis of murine dermal lymphatic endothelial cells (LECs), we identified Foxp2 , a member of the FOXP family of transcription factors implicated in speech development, as a collecting vessel signature gene. FOXP2 expression was induced after initiation of lymph flow in vivo and upon shear stress on primary LECs in vitro . Loss of FOXC2, the major flow‐responsive transcriptional regulator of lymphatic valve formation, abolished FOXP2 induction in vitro and in vivo . Genetic deletion of Foxp2 in mice using the endothelial‐specific Tie2‐Cre or the tamoxifen‐inducible LEC‐specific Prox1‐CreER T2 line resulted in enlarged collecting vessels and defective valves characterized by loss of NFATc1 activity. Our results identify FOXP2 as a new flow‐induced transcriptional regulator of collecting lymphatic vessel morphogenesis and highlight the existence of unique transcription factor codes in the establishment of vessel‐type‐specific endothelial cell identities.

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Section: Foxp2 Expression Is Regulated By Flowsupporting

confidence: 61%

Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

et al. 2021

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“…In line with this, lymphatic endothelial-specific deletion of heparan sulfates leads to attenuation of tumor-induced lymphangiogenesis, possibly because of decreased VEGFR3 signaling (Johns et al 2016). Strikingly, however, syndecan-4 deletion led to excessive expansion of lymphatic vasculature during embryonic development (Wang et al 2016), suggesting that syndecan-4 is not needed for VEGFR3 signaling, at least in the developmental setting. Furthermore, a chimeric VEGF-C containing the VEGF homology domain of VEGF-C in fusion with the high-affinity heparan sulfate-binding domain of VEGF induced a unique lymphatic vessel growth pattern along blood vessels (Tammela et al 2007).…”

Section: The Vegf-c-vegfr3 Signaling Complex In Lymphangiogenesismentioning

confidence: 76%

“…The endothelial transmembrane protein PECAM1 (CD31) functions as a mechanosensor in BEC-BEC junctions of the blood vascular endothelium (Osawa et al 2002;Tzima et al 2005). Interestingly, Pecam1-deleted mouse embryos have increased branching of mesenteric lymphatics, suggesting that PECAM1 could provide a similar function also in the lymphatic vessels (Wang et al 2016). Furthermore, loss of syndecan-4 or β-catenin function leads to defective lymphatic vasculature patterning in the embryonic mesentery and dermis, respectively (Cha et al 2016;Wang et al 2016).…”

Section: Lymphatic Vessel Sproutingmentioning

confidence: 99%

“…Interestingly, Pecam1-deleted mouse embryos have increased branching of mesenteric lymphatics, suggesting that PECAM1 could provide a similar function also in the lymphatic vessels (Wang et al 2016). Furthermore, loss of syndecan-4 or β-catenin function leads to defective lymphatic vasculature patterning in the embryonic mesentery and dermis, respectively (Cha et al 2016;Wang et al 2016). These mutant phenotypes may be caused by defective flow sensing, which leads to increased proliferation of LECs or lack of pruning of the lymphatic sprouts, resembling the defective blood vessel pruning in decreased flow conditions (for review, see Korn and Augustin 2015).…”

Section: Lymphatic Vessel Sproutingmentioning

confidence: 99%

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Lymphangiogenesis guidance by paracrine and pericellular factors

et al. 2017

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Lymphatic vessels are important for tissue fluid homeostasis, lipid absorption, and immune cell trafficking and are involved in the pathogenesis of several human diseases. The mechanisms by which the lymphatic vasculature network is formed, remodeled, and adapted to physiological and pathological challenges are controlled by an intricate balance of growth factor and biomechanical cues. These transduce signals for the readjustment of gene expression and lymphatic endothelial migration, proliferation, and differentiation. In this review, we describe several of these cues and how they are integrated for the generation of functional lymphatic vessel networks.

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“…We, among others, uncovered a potential role for syndecans, members of the proteoglycan family, in this respect. Indeed, deletion of syndecans is associated with a lack of endothelial cell alignment in the direction of flow [33,95,96] and the development of atherosclerotic lesions in areas where blood flow is normally atheroprotective [33]. This deletion did not suppress flow sensing but rather only affected the repression of inflammatory responses associated with flow, in addition to endothelial cell polarity [33].…”

Section: Cell Biology Of Flow Sensing: Recent Insights Into An Intricmentioning

confidence: 99%

Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction

Baeyens

2018

Biochemical Pharmacology

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Blood circulation, facilitating gas exchange and nutrient transportation, is a quintessential feature of life in vertebrates. Any disruption to blood flow, may it be by blockade or traumatic rupture, irrevocably leads to tissue infarction or death. Therefore, it is not surprising that hemostasis and vascular adaptation measures have been evolutionarily selected to mitigate the adverse consequences of altered circulation. Blood vessels can be broadly categorized as arteries, veins, or capillaries, based on their structure, hemodynamics, and gas exchange. However, all of them share one property: they are lined with an epithelial sheet called the endothelium, which typically lies on a basement membrane. This endothelium is the primary interface between the flowing blood and the rest of the body, and it has highly specialized molecular mechanisms to detect and respond to changes in blood perfusion. The purpose of this commentary will be to highlight some of the recent developments in the research on blood flow sensing, vascular remodeling, and homeostasis and to discuss the development of innovative pharmaceutical approaches targeting mechanosensing mechanisms to prolong patient survival and improve quality of life. 1. Introduction: physiology of blood flow sensation and adaptation One of the earliest observations of vascular adaptation in response to changes in hemodynamics was made in the nineteenth century by Thoma and these were further investigated by Chapman and Murray in the chick yolk sac; adequate perfusion was found to determine which premature, non-perfused, and unspecified vessels undergo arterial specification and maturation, while under-perfused vessels remain closed and regress [1-3]. These earlier observations are striking: blood vessels are not merely biological pipes, they are dynamic structures shaped by blood flow itself. This dynamic adaptation is not restrained to the developmental stages of the vasculature, with a transient increase in arterial flow being associated with a transient dilation of the mature arteries under increased flow, through vasorelaxant release [4-8]. Furthermore, a sustained increase in flow, as observed in the muscular arteries of physically trained individuals [9,10] or in the uterine artery during pregnancy [11,12], triggers active remodeling of the concerned arteries by increasing their lumen diameter, improving tissue perfusion. Similarly, hypoperfusion of mature blood vessels, following stenosis for example, leads to the inward remodeling of under-perfused vessels. Interestingly, this inward remodeling could not be linked to an increased contraction of the mural cells as vasorelaxants could not relieve it [13]. This indicates a more profound, structural adaptation of the vessel in response to changes in flow. This was later confirmed after observing that mice lacking matrix metalloproteinases could not undergo successful inward remodeling in response to decreased flow due to the lack of remodeling of the collagen matrix [14,15]. These observations, in various animal m...

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Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development

Cited by 8 publications

References 12 publications

Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

Transcription factor FOXP2 is a flow‐induced regulator of collecting lymphatic vessels

Lymphangiogenesis guidance by paracrine and pericellular factors

Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction

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