Mechanisms of Vessel Branching

Smet, Frederik De; Segura, Inmaculada; Bock, Katrien De; Hohensinner, Philipp J.; Carmeliet, Peter

doi:10.1161/atvbaha.109.185165

Cited by 334 publications

(258 citation statements)

References 104 publications

(192 reference statements)

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“…Although VEGF activation has been implicated in the formation endothelial tip cell filopodia, our understanding of the elaboration of filopodia in ECs remains incomplete (De Smet et al. 2009; Siekman et al. 2013).…”

Section: Discussionmentioning

confidence: 99%

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

et al. 2016

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Platelet endothelial cell adhesion molecule (PECAM‐1) has been implicated in angiogenesis through processes that involve stimulation of endothelial cell motility. Previous studies suggest that PECAM‐1 tyrosine phosphorylation mediates the recruitment and then activation of the tyrosine phosphatase SHP‐2, which in turn promotes the turnover of focal adhesions and the extension of filopodia, processes critical to cell motility. While these studies have implicated PECAM‐1‐dependent signaling in PECAM‐1‐mediated cell motility, the involvement of PECAM‐1 ligand binding in cell migration is undefined. Therefore to investigate the role of PECAM‐1 binding interactions in cell motility, mutants of PECAM‐1 were generated in which either homophilic or heparin/glycosaminoglycan (GAG)‐mediated heterophilic binding had been disabled and then expressed in an endothelial cell surrogate. We found that the ability of PECAM‐1 to stimulate cell migration, promote filopodia formation and trigger Cdc42 activation were lost if PECAM‐1‐dependent homophilic or heparin/GAG‐dependent heterophilic ligand binding was disabled. We further observed that PECAM‐1 concentrated at the tips of extended filopodia, an activity that was diminished if homophilic, but not heparin/GAG‐mediated heterophilic binding had been disrupted. Similar patterns of activities were seen in mouse endothelial cells treated with antibodies that specifically block PECAM‐1‐dependent homophilic or heterophilic adhesion. Together these data provide evidence for the differential involvement of PECAM‐1‐ligand interactions in PECAM‐1‐dependent motility and the extension of filopodia.

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Section: Discussionmentioning

confidence: 99%

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

et al. 2016

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“…In particular, we neglect the distinction between veins and arteries; 2) oxygen-depleted areas of a tissue become hypoxic by simple thresholding depending on the local partial pressure of oxygen; 3) hypoxic tissue starts to secrete a single long-diffusion-length isoform of VEGF-A, like VEGF-A 120,121 . The molecular HIF-1-dependent cascades resulting in VEGF-A production are not explicitly included in the model; 4) VEGF-A activity induces a dosedependent activation of the ECs forming the external walls of the preexisting vessels; 5) we include tip cell selection and stalk cell lateral inhibition without explicitly modeling the delta-notch signaling pathways; 6) the tip cells respond to VEGF-A by polarizing and chemotactically migrating, while the stalk individuals respond by proliferating [13]; 7) the tip/stalk cell fate is reversible, in the sense that a tip cell can assume a stalk state after anastomosis and a stalk cell can acquire a tip fate if it is not surrounded by tip individuals. In this last case, we do not consider recovery delays, which are due to the time needed by stalk cell gene expression to return in a normal non-inhibited state; 8) both type of activated vascular endothelial cells secrete and chemotax towards a short-diffusion-length chemoattractant (which can represent for instance VEGF-A 165 [60]); 9) oxygen is assumed to be secreted both by the functional preexisting vasculature and by emerging loop structures.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…In particular, v(Σ σ , t) = x∈Σσ v(x, t) and c(Σ σ , t) = x∈Σσ c(x, t) measure the total amounts inside cell Σ σ of the tissue-secreted VEGF-A and of the ECproduced chemoattractant, respectively, as v(x, t) and c(x, t) are their local concentrations defined in Eqs. (12) and (13). In particular, in (2), we account the fact that the short-range autocrine chemical induces a migratory response in both tip and stalk cells, whereas the long-range VEGF-A only in tip ECs (due to the delta/notch-mediated lateral inhibition of VEGFdependent motility in stalk individuals).…”

Section: Mathematical Modelmentioning

confidence: 99%

“…The overall process starts when tissue cells, deprived of oxygen and/or nutrients, accumulate in the nucleus increasing amounts of hypoxic growth factor (HIF-1). By selected binding to DNA, HIF-1 is able to regulate the expression levels of numerous genes, which control the production of a wide range of angiogenic growth factors [13,29], including vascular endothelial growth factors (VEGFs), transforming growth factor β (TGF-β), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF). Such diffusive chemicals in turn stimulate the endothelial cells forming the external walls of preexisting blood vessels, which loosen their adhesive connections, thereby reducing the vascular tonus and increasing both the permeability the interstitial pressure.…”

Section: Introductionmentioning

confidence: 99%

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A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue

Scianna

Bassino

Munaron

2015

Computers in Biology and Medicine

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Angiogenesis, the formation of new blood vessel networks from existing capillary or post-capillary venules, is an intrinsically multiscale process occurring in several physio-pathological conditions. In particular, hypoxic tissue cells activate downstream cascades culminating in the secretion of a wide range of angiogenic factors, including VEGF isoforms. Such diffusive chemicals activate the endothelial cells (ECs) forming the external walls of the nearby vessels, that chemotactictally migrate toward the hypoxic areas of the tissue as multicellular sprouts. A functional network eventually emerges by further branching and anastomosis processes. We here propose a CPM-based approach reproducing selected features of the angiogenic progression necessary for the reoxygenation of a hypoxic tissue. Our model is able to span the different scale involved in the angiogenic progression as it incorporates reaction-diffusion equations for the description of the evolution of microenvironmental variables in a discrete mesoscopic cellular Potts model (CPM) that reproduces the dynamics of the vascular cells. A key feature of this work is the explicit phenotypic differentiation of the ECs themselves, distin-1 E-Mail: marcosci1@alice.it 2 E-Mail: eleonora.bassino@unito.it 3 E-Mail: luca.munaron@unito.it Preprint submitted to Computers in Biology and Medicine May 25, 2015 guished in quiescent, stalk and tip. The simulation results allow identifying a set of key mechanisms underlying tissue vascularization. Further, we provide evidence that the nascent pattern is characterized by precise topological properties. Finally, we link abnormal sprouting angiogenesis with alteration in selected cell behavior.

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“…Another phenotype associated with loss of SRF in ECs was the disruption of the actin cytoskeleton in the so-called tip cells, 48 which give rise to sprouting ECs during angiogenesis. 47 This resulted in defective angiogenic sprouting and expansion of subjacent stalk cells, which could underlie the aneurysm phenotype. 48 It will be informative to delete SRF in adult ECs to further illuminate the role of this transcription factor in postnatal angiogenic responses.…”

Section: Blood Vesselsmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

119

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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Mechanisms of Vessel Branching

Cited by 334 publications

References 104 publications

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue

Role of serum response factor in the pathogenesis of disease

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