Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor‐C

Alderfer, Laura; Russo, Elizabeth; Archilla, Adriana; Coe, Brian C.; Hanjaya‐Putra, Donny

doi:10.1096/fj.202002426rr

Cited by 37 publications

(72 citation statements)

References 60 publications

(168 reference statements)

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“…Changes in ECM composition and matrix stiffness have dynamic effects on vascular signaling (63) and increases in collagen density impaired neovessel length and interconnectivity in an in vitro model of sprouting angiogenesis (64). Similarly, recent evidence has shown that reduced matrix stiffness primes lymphatic endothelial cells to form cord-like structures and increase the expression of lymphatic markers such as LYVE-1 and PROX1 in vitro in response to VEGF-C (65) and promote increased GATA2 expression and GATA2- dependent upregulation of genes involved in cell migration and lymphangiogenesis (66). Notably, we show increased expression of MMP-2 in tissues of the anterior segment of NC- Foxc2 -/- mice ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Differential roles of neural crest- and endothelial-derived FOXC2 in trabecular meshwork and Schlemm’s Canal in glaucomatous pathology

Norden

Beckmann

Fang

et al. 2022

Preprint

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Impaired development and maintenance of the Schlemm’s Canal (SC) is associated with perturbed aqueous humor outflow regulation and glaucoma progression. Key molecular mechanisms, such as ANGPT/TIE2, PROX1, and VEGF-C/VEGFR-3 regulate SC development and maintenance, but mechanisms of paracrine signaling from neighboring tissues, including the trabecular meshwork (TM) are poorly understood. Here, we show Foxc2 is critical within the neural crest (NC)-derived TM and SC endothelium for development of the aqueous humor outflow pathway. In mice, NC-specific deletion of Foxc2 results in abnormal anterior eye segment development, including impaired SC morphogenesis and functional maintenance, loss of SC identity, and impaired maintenance of intraocular pressure (IOP). Visible light optical coherence tomography angiography analysis also demonstrated functional impairment of the SC in response to changes in IOP in NC-Foxc2-/- mice, suggesting increased TM stiffness. Utilization of single-cell RNA-sequencing (scRNA-seq) analysis then identified that this phenotype is predominately characterized by transcriptional changes associated with extracellular matrix organization and stiffness in TM-associated cell clusters, including increased matrix metalloproteinase (MMP) expression, which can generate soluble TIE2 that acts as an ANGPT trap. As FOXC2 is also critically involved in development of the lymphatic vasculature in other tissues, we also show that endothelial-specific deletion of Foxc2 resulted in impaired SC morphogenesis due to loss of TIE2 expression, which was rescued by deletion of the TIE2 phosphatase VE-PTP. Thus, NC-Foxc2 is critical for development of the TM, and both NC- and endothelial-Foxc2 are key for maintenance of SC identity and its morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Differential roles of neural crest- and endothelial-derived FOXC2 in trabecular meshwork and Schlemm’s Canal in glaucomatous pathology

Norden

Beckmann

Fang

et al. 2022

Preprint

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“…For example, a stiff extracellular matrix may negatively influence LEC responsiveness to VEGF-C. This is suggested by the ability of soft matrices to increase VEGFR3 expression via GATA2 regulation in LECs [34], and to promote VEGF-C-driven LEC tube formation in hydrogels [128]. Fibrosis and excessive collagen deposition have also been associated with obliteration of lymphatic vessel lumens, thereby contributing to reduced lymphatic function [129].…”

Section: Box 2 Current Treatment Options For Lymphedemamentioning

confidence: 99%

Homeostatic maintenance of the lymphatic vasculature

Stritt

Koltowska

Mäkinen

2021

Trends in Molecular Medicine

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“…In the development of the lymphatic system, ECM stiffness has a strong impact; a soft ECM is essential for lymphatic vessel formation through regulation of GATA Binding Protein 2 (GATA2) and the subsequent downregulation of TGFβ2 [141]. Moreover, it was shown recently that different pathways regulating the formation of lymphatic cord-like structures in an in vitro system can be tuned by different matrix stiffnesses together with VEGF-C concentrations [142].…”

Section: Mechano-transductionmentioning

confidence: 99%

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

Ponomarev

Ksiazkiewicz

Staring

et al. 2021

IJMS

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Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.

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Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor‐C

Cited by 37 publications

References 60 publications

Differential roles of neural crest- and endothelial-derived FOXC2 in trabecular meshwork and Schlemm’s Canal in glaucomatous pathology

Differential roles of neural crest- and endothelial-derived FOXC2 in trabecular meshwork and Schlemm’s Canal in glaucomatous pathology

Homeostatic maintenance of the lymphatic vasculature

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

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