Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport

Wu, Florence T.H.; Stefanini, Marianne O.; Gabhann, Feilim Mac; Kontos, Christopher D.; Annex, Brian H.; Popel, Aleksander S.

doi:10.1152/physiolgenomics.00031.2009

Cited by 19 publications

(21 citation statements)

References 42 publications

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“…At high calf secretion rate of VEGF, increasing calf secretion rate of sVEGFR1 began to increase interstitial VEGF globally (normal compartment); at high calf secretion rate of sVEGFR1, increasing calf secretion rate of VEGF began to decrease circulating sVEGFR1 (blood compartment). In general, most of the net flow directions in this PAD model were conserved relative to the healthy model, such that we expect the preservation of the mechanism whereby sVEGFR1 shuttles interstitial VEGF into the plasma (80).…”

Section: Pad-specific System Responses To Upregulated Protein Expressmentioning

confidence: 88%

“…In recent model extensions, we developed whole body multicompartmental models for predicting the systemic distributions of VEGF and sVEGFR1 in healthy human subjects between three major compartments: the calf muscle, blood, and the rest of the body (70,80,81). Model features included detailed biomolecular interactions between VEGF 121 , VEGF 165 , VEGFR1, VEGFR2, NRP1, sVEGFR1, and interstitial matrix binding sites, as well as intercompartmental macromolecular transport through vascular permeability, lymphatic drainage, and direct plasma clearance.…”

Section: Computational Modeling: Objectives and Achievementsmentioning

confidence: 99%

“…This human PAD model was based on the mathematical formulation used for our previous compartmental models (70,80,81; see supplemental material for complete mathematical equations); the solution of a system of 59 coupled nonlinear ordinary differential equations predicts changes in molecular concentrations over time as a function of binding and transport kinetic constants. In the equations, all blood and tissue concentrations of molecular species X are expressed in the notations of [X] j (mol/cm 3 of tissue j; j ϭ N for Normal or D for PAD calf) and [X]B (mol/cm 3 of blood), respectively.…”

Section: Mathematical Formulation and Notationsmentioning

confidence: 99%

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VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model

Stefanini

Gabhann

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, the growth of new capillaries from existing microvasculature. In peripheral arterial disease (PAD), lower extremity muscle ischemia develops downstream of atherosclerotic obstruction. A working hypothesis proposed that the maladaptive overexpression of soluble VEGF receptor 1 (sVEGFR1) in ischemic muscle tissues, and its subsequent antagonism of VEGF bioactivity, may contribute to the deficient angiogenic response in PAD, as well as the limited success of therapeutic angiogenesis strategies where exogenous VEGF genes/proteins are delivered. The objectives of this study were to develop a computational framework for simulating the systemic distributions of VEGF and sVEGFR1 (e.g., intramuscular vs. circulating, free vs. complexed) as observed in human PAD patients and to serve as a platform for the systematic optimization of diagnostic tools and therapeutic strategies. A three-compartment model was constructed, dividing the human body into the ischemic calf muscle, blood, and the rest of the body, connected through macromolecular biotransport processes. Detailed molecular interactions between VEGF, sVEGFR1, endothelial surface receptors (VEGFR1, VEGFR2, NRP1), and interstitial matrix sites were modeled. Our simulation results did not support a simultaneous decrease in plasma sVEGFR1 during PAD-associated elevations in plasma VEGF reported in literature. Furthermore, despite the overexpression in sVEGFR1, our PAD control demonstrated increased proangiogenic signaling complex formation, relative to our previous healthy control, due to sizeable upregulations in VEGFR2 and VEGF expression, thus leaving open the possibility that impaired angiogenesis in PAD may be rooted in signaling pathway disruptions downstream of ligand-receptor binding.

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Section: Pad-specific System Responses To Upregulated Protein Expressmentioning

confidence: 88%

Section: Computational Modeling: Objectives and Achievementsmentioning

confidence: 99%

Section: Mathematical Formulation and Notationsmentioning

confidence: 99%

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VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model

Stefanini

Gabhann

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…The VEGF in those tissues comes primarily from the parenchymal and stromal cells of that tissue (134, 142, 143). VEGF in the bloodstream is primarily a result of clearance and extravasation from tissues and plasma clearance; we have predicted the role of luminal VEGF secretion by the endothelium in recent models (144).…”

Section: In Vivo Spatial Patterning Of Vegf Isoform Gradientsmentioning

confidence: 99%

“…Based on experimental (146) and theoretical studies (50, 143), a fraction of VEGF from parenchymal cells is either captured and internalized by endothelial cells or degraded in the interstitium. Pharmacokinetic models show that anti-VEGF agents have a dispersive effect, similar to that of proteolytic release of VEGF.…”

Section: In Vivo Spatial Patterning Of Vegf Isoform Gradientsmentioning

confidence: 99%

Extracellular regulation of VEGF: Isoforms, proteolysis, and vascular patterning

Vempati¹,

Popel²,

Gabhann³

2014

Cytokine & Growth Factor Reviews

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258

230

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The regulation of vascular endothelial growth factor A (VEGF) is critical to neovascularization in numerous tissues under physiological and pathological conditions. VEGF has multiple isoforms, created by alternative splicing or proteolytic cleavage, and characterized by different receptor-binding and matrix-binding properties. These isoforms are known to give rise to a spectrum of angiogenesis patterns marked by differences in branching, which has functional implications for tissues. In this review, we detail the extensive extracellular regulation of VEGF and the ability of VEGF to dictate the vascular phenotype. We explore the role of VEGF-releasing proteases and soluble carrier molecules on VEGF activity. While proteases such as MMP9 can ‘release’ matrix-bound VEGF and promote angiogenesis, for example as a key step in carcinogenesis, proteases can also suppress VEGF’s angiogenic effects. We explore what dictates pro- or anti-angiogenic behavior. We also seek to understand the phenomenon of VEGF gradient formation. Strong VEGF gradients are thought to be due to decreased rates of diffusion from reversible matrix binding, however theoretical studies show that this scenario cannot give rise to lasting VEGF gradients in vivo. We propose that gradients are formed through degradation of sequestered VEGF. Finally, we review how different aspects of the VEGF signal, such as its concentration, gradient, matrix-binding, and NRP1-binding can differentially affect angiogenesis. We explore how this allows VEGF to regulate the formation of vascular networks across a spectrum of high to low branching densities, and from normal to pathological angiogenesis. A better understanding of the control of angiogenesis is necessary to improve upon limitations of current angiogenic therapies.

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Stimulus–responsive ultrasound contrast agents for clinical imaging: motivations, demonstrations, and future directions

Goodwin

Nakatsuka

Mattrey

2014

WIREs Nanomed Nanobiotechnol

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Microbubble ultrasound contrast agents allow imaging of the vasculature with excellent resolution and signal-to-noise ratios. Contrast in microbubbles derives from their interaction with an ultrasound wave to generate signal at harmonic frequencies of the stimulating pulse; subtracting the elastic echo caused by the surrounding tissue can enhance the specificity of these harmonic signals significantly. The nonlinear acoustic emission is caused by pressure-driven microbubble size fluctuations, which in both theoretical descriptions and empirical measurements was found to depend on the mechanical properties of the shell that encapsulates the microbubble as well as stabilizes it against the surrounding aqueous environment. Thus biochemically-induced switching between a rigid “off” state and a flexible “on” state provides a mechanism for sensing chemical markers for disease. In our research, we coupled DNA oligonucleotides to a stabilizing lipid monolayer to modulate stiffness of the shell and thereby induce stimulus-responsive behavior. In initial proof-of-principle studies, it was found that signal modulation came primarily from DNA crosslinks preventing the microbubble size oscillations rather than merely damping the signal. Next, these microbubbles were redesigned to include an aptamer sequence in the crosslinking strand, which not only allowed the sensing of the clotting enzyme thrombin but also provided a general strategy for sensing other soluble biomarkers in the bloodstream. Finally, the thrombin-sensitive microbubbles were validated in a rabbit model, presenting the first example of an ultrasound contrast agent that could differentiate between active and inactive clots for the diagnosis of Deep Venous Thrombosis.

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Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport

Cited by 19 publications

References 42 publications

VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model

VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model

Extracellular regulation of VEGF: Isoforms, proteolysis, and vascular patterning

Stimulus–responsive ultrasound contrast agents for clinical imaging: motivations, demonstrations, and future directions

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