Proteolytic Processing Regulates Placental Growth Factor Activities

Hoffmann, Daniel C.; Willenborg, Sebastian; Koch, Manuel; Zwolanek, Daniela; Müller, Stefan; Becker, Ann Kathrin A.; Metzger, Stéphanie; Ehrbar, Martin; Kurschat, Peter; Hellmich, Martin; Hubbell, Jeffrey A.; Eming, Sabine A.

doi:10.1074/jbc.m113.451831

Cited by 20 publications

(13 citation statements)

References 41 publications

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“…Though we have not previously included PlGF in a compartment model, PlGF binding to VEGFR1 has been modeled in vitro [45], and the parameter values are matched to this study. The affinity of PlGF2 for NRP1 is based on experimental measurements of PlGF2 binding to the NRP1 extracellular domain [65]. Slightly different affinities are used for VEGF binding to matrix sites and to NRP1 than in previous compartment models, in order to use measurements from a single source for both VEGF 165 and VEGF 189 (NRP1-binding) [64], or for VEGF and PlGF (matrix-binding) [66].…”

Section: Methodsmentioning

confidence: 99%

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands

Clegg

Gabhann

2017

PLoS Comput Biol

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The splice isoforms of vascular endothelial growth A (VEGF) each have different affinities for the extracellular matrix (ECM) and the coreceptor NRP1, which leads to distinct vascular phenotypes in model systems expressing only a single VEGF isoform. ECM-immobilized VEGF can bind to and activate VEGF receptor 2 (VEGFR2) directly, with a different pattern of site-specific phosphorylation than diffusible VEGF. To date, the way in which ECM binding alters the distribution of isoforms of VEGF and of the related placental growth factor (PlGF) in the body and resulting angiogenic signaling is not well-understood. Here, we extend our previous validated cell-level computational model of VEGFR2 ligation, intracellular trafficking, and site-specific phosphorylation, which captured differences in signaling by soluble and immobilized VEGF, to a multi-scale whole-body framework. This computational systems pharmacology model captures the ability of the ECM to regulate isoform-specific growth factor distribution distinctly for VEGF and PlGF, and to buffer free VEGF and PlGF levels in tissue. We show that binding of immobilized growth factor to VEGF receptors, both on endothelial cells and soluble VEGFR1, is likely important to signaling in vivo. Additionally, our model predicts that VEGF isoform-specific properties lead to distinct profiles of VEGFR1 and VEGFR2 binding and VEGFR2 site-specific phosphorylation in vivo, mediated by Neuropilin-1. These predicted signaling changes mirror those observed in murine systems expressing single VEGF isoforms. Simulations predict that, contrary to the ‘ligand-shifting hypothesis,’ VEGF and PlGF do not compete for receptor binding at physiological concentrations, though PlGF is predicted to slightly increase VEGFR2 phosphorylation when over-expressed by 10-fold. These results are critical to design of appropriate therapeutic strategies to control VEGF availability and signaling in regenerative medicine applications.

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Section: Methodsmentioning

confidence: 99%

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands

Clegg

Gabhann

2017

PLoS Comput Biol

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“…Deprivation of proangiogenic factors, such as members of the vascular endothelial growth factor (VEGF) family, by proteolytic degradation and subsequent interference with their bioactivity in the hostile chronic wound microenvironment has been suggested as a critical underlying cause (41, 50). In pressure ulcers, chemokine (C-X-C motif) ligand 9 expression levels fail to increase as they do in healthy, healing wounds (51), leading to inhibition of endothelial cell chemotaxis at the proliferative stage of angiogenesis and subsequently aberrant angiogenesis (52).…”

Section: Wound-healing Pathologymentioning

confidence: 99%

Wound repair and regeneration: Mechanisms, signaling, and translation

2014

Self Cite

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The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body’s natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.

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“…Recent reviews and original reports have noted the interrelationship of immunity with tissue repair and in some cases with regeneration . Certainly diverse leukocyte lineages are attracted to sites of burn damage where they act both as sensors and effectors as they coordinate skin damage during the early period and then set the stage for resolution of injury . The application of proteomic tools to this temporal period provides supporting evidence that hypertrophic scars are indeed continuing to generate unique proteomic profiles and these are not merely a continuation of the same protein expression profiles that characterize the human burn wound in its acute reparative phase.…”

Section: Discussionmentioning

confidence: 99%

Imaging mass spectrometry for accessing molecular changes during burn wound healing

Taverna

Pollins

Sindona

et al. 2016

Wound Repair Regeneration

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The spatiotemporal analysis of the proteomic profile during human wound healing is a critical investigative step that can establish the complex interplay of molecular events that comprise the local response to burn injury. Partial-thickness wound samples with adjacent "normal" skin were collected from twenty-one patients with burn wounds and examined across a time spectrum ranging from the acute injury period at 3, 6, 11 days to the later hypertrophic scar period at 7 and 15 months. The techniques used for histology-directed tissue analyses highlighted inflammatory protein markers at the early time points after injury with diminished expression as burn wounds progressed into the proliferative phase. The datasets show the usefulness of MALDI MS and imaging mass spectrometry as discovery approaches to identify and map the cutaneous molecular sequence that is activated in response to the unique systemic inflammatory response following burn trauma. This information has the potential to define the unique factors that predispose human burn victims to disfiguring hypertrophic scar formation.

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Proteolytic Processing Regulates Placental Growth Factor Activities

Cited by 20 publications

References 41 publications

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands

Wound repair and regeneration: Mechanisms, signaling, and translation

Imaging mass spectrometry for accessing molecular changes during burn wound healing

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