Heparan Sulfate in trans Potentiates VEGFR-Mediated Angiogenesis

Jakobsson, Lars; Kreuger, Johan; Holmborn, Katarina; Lundin, Lars; Eriksson, Inger; Kjellén, Lena; Claesson‐Welsh, Lena

doi:10.1016/j.devcel.2006.03.009

Cited by 220 publications

(197 citation statements)

References 42 publications

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“…1) that confer on those isoforms an ability to bind to, and be sequestered by, proteoglycans of the extracellular matrix 5 or cell surface (HSPGs). 3 , 6 , 7 Second, the ‘xxxa’ isoforms contain the short C-terminal exon 8a-encoded sequence, which can confer the ability to bind to the Neuropilin coreceptors (Fig. 1, 2), while the ‘xxxb’ isoforms, containing the exon 8b-encoded sequence, cannot.…”

Section: Vegf-a Isoforms Exhibit Differential Binding To Vegfrs and Nrpsmentioning

confidence: 99%

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

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Section: Vegf-a Isoforms Exhibit Differential Binding To Vegfrs and Nrpsmentioning

confidence: 99%

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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“…HSPGs generally are thought to regulate growth factor signaling on the surface of the signal-receiving cells (5). It has been reported, however, that HSPGs can regulate signaling in trans from neighboring cells in some cases (6,7).…”

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confidence: 99%

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

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We previously proposed a model that DALLY, a Drosophila glypican, acts as a trans co-receptor to regulate BMP signaling in the germ line stem cell niche. To investigate the molecular mechanisms of contact-dependent BMP signaling, we developed novel in vitro assay systems to monitor trans signaling using Drosophila S2 cells. Using immunoblot-based as well as single-cell assay systems, we present evidence that Drosophila glypicans indeed enhance BMP signaling in trans in a contactdependent manner in vitro. Our analysis showed that heparan sulfate modification is required for the trans co-receptor activity of DALLY. Two BMP-like molecules, Decapentaplegic (DPP) and Glass bottom boat, can mediate trans signaling through a heparan sulfate proteoglycan co-receptor in S2 cells. The in vitro systems reflect the molecular characteristics of heparan sulfate proteoglycan functions observed previously in vivo, such as ligand specificity and biphasic activity dependent on the ligand dosage. In addition, experiments using a DALLY-coated surface suggested that DALLY regulates DPP signaling in trans by its effect on the stability of DPP protein on the surface of the contacting cells. Our findings provide the molecular foundation for novel contact-dependent signaling, which defines the physical space of the stem cell niche in vivo. Bone morphogenetic proteins (BMPs)2 play critical roles in cell-cell communication during animal development. Remarkably, these molecules mediate both long and short range signaling dependent on context. For example, Decapentaplegic (DPP), a Drosophila homologue of BMPs, acts as a long range morphogen in the developing wing and as a contact-dependent niche factor in the female germ line stem cell (GSC) niche. The molecular basis underlying this differential activity of BMPs is not fully understood.Signaling and distribution of BMPs in a tissue are modulated by a class of carbohydrate-modified molecules, heparan sulfate proteoglycans (HSPGs) (1-3). In addition to BMPs, HSPGs serve as co-receptors for a number of other growth factors and morphogens, including FGF, WNT, and Hedgehog (4). HSPGs generally are thought to regulate growth factor signaling on the surface of the signal-receiving cells (5). It has been reported, however, that HSPGs can regulate signaling in trans from neighboring cells in some cases (6, 7).Recent studies demonstrated that HSPGs are essential regulators of the GSC niche in the Drosophila ovary (8, 9). Although it has been well established that DPP regulates the asymmetric division of a GSC (10), the mechanism by which this secreted molecule differentially regulates two daughter cells has been a mystery. We have found previously that DALLY, a Drosophila HSPG of the glypican type, is expressed specifically in the somatic niche cells (the cap cells) contacting GSCs and is required for GSC maintenance (8). Ectopic dally expression in somatic cells in a wide region of the germarium was sufficient to maintain all the contacting germ line cells as GSC-like undifferentiated cells, thus e...

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“…VEGFA165 is thought to be the most abundantly expressed splice form with the capacity to interact both with neuropilins and HSPGs, whereas the shorter splice form VEGFA121 does not interact with HSPGs or neuropilins (13)(14)(15)(16). Interactions between VEGFA165 and HSPG coreceptors are required for proper gradient formation in tissues, and these interactions probably also influence the kinetics and the quality of VEGFR2 signaling (13,17). However, it has been rather difficult to record long range gradients of VEGFA165 similar to what has been shown for morphogens in various model systems (14,18,19).…”

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confidence: 99%

Endothelial Cell Migration in Stable Gradients of Vascular Endothelial Growth Factor A and Fibroblast Growth Factor 2

Barkefors

Jan

Jakobsson

et al. 2008

Journal of Biological Chemistry

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Gradients of secreted signaling proteins guide growing blood vessels during both normal and pathological angiogenesis. However, the mechanisms by which endothelial cells integrate and respond to graded distributions of chemotactic factors are still poorly understood. We have in this study investigated endothelial cell migration in response to hill-shaped gradients of vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 2 (FGF2) using a novel microfluidic chemotaxis chamber (MCC). Cell migration was scored at the level of individual cells using time-lapse microscopy. A stable gradient of VEGFA165 ranging from 0 to 50 ng/ml over a distance of 400 m was shown to strongly induce chemotaxis of endothelial cells of different vascular origin. VEGFA121, unable to bind proteoglycan and neuropilin coreceptors, was also shown to induce chemotaxis in this setup. Furthermore, a gradient of FGF2 was able to attract venular but not arterial endothelial cells, albeit less efficiently than VEGFA165. Notably, constant levels of VEGFA165, but not of FGF2, were shown to efficiently reduce chemokinesis. Systematic exploration of different gradient shapes led to the identification of a minimal gradient steepness required for efficient cell guidance. Finally, analysis of cell migration in different regions of the applied gradients showed that chemotaxis is reduced when cells reach the high end of the gradient. Our findings suggest that chemotactic growth factor gradients may instruct endothelial cells to shift toward a nonmigratory phenotype when approaching the growth factor source.Many cells in developing organs and tissues have the capacity to detect extracellular chemical gradients and to respond to these gradients by directed positive or negative migration, a process called chemotaxis. In addition, some factors may also regulate chemokinesis which refers to nondirectional cell migration. Directed cell migration is at the heart of embryonic blood vessel formation, where the growing vessels navigate by a combination of secreted chemoattractants and repellents. The leading front of the embryonic vascular sprout holds a tip cell with numerous filopodia that express receptors for sensing secreted and cell-bound guidance cues provided by surrounding cells (1). One of the most well studied factors that control blood vessel formation and function is vascular endothelial growth factor A (VEGFA) 2 (2-5). The effects of VEGFA on endothelial cells have been intensely studied for many years in an array of different model systems (4, 6 -9). However, the ability to generate and maintain stable gradients of soluble factors compatible with cell culture conditions was only recently made possible by the invention of a microfluidic chemotaxis chamber (MCC). Chemotaxis of several cell types, including neutrophils and cancer cells, have been successfully studied in MCCs, but the method has so far not been used to systematically study endothelial cell migration in gradients of chemotactic factors (10, 11).VEGF receptor 2 (VEGFR2) i...

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Heparan Sulfate in trans Potentiates VEGFR-Mediated Angiogenesis

Cited by 220 publications

References 42 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Endothelial Cell Migration in Stable Gradients of Vascular Endothelial Growth Factor A and Fibroblast Growth Factor 2

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