Endothelial Von Willebrand factor regulates angiogenesis

Starke, Richard; Paschalaki, Koralia; Ferraro, Francesco; Dryden, Nicola H.; McKinnon, Thomas A. J.; Sutton, Rachel E.; Payne, Elspeth; Haskard, Dorian O.; Hughes, Alun D.; Cutler, Daniel; Laffan, Mike; Randi, Anna M.

doi:10.1016/j.vph.2011.08.038

Cited by 127 publications

(223 citation statements)

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“…6H). In this assay, Ang2 stimulated cell motility on gelatin, which is recognized by avb3 rather than a2b1 integrins in HUVECs (Rüegg et al, 1998;Starke et al, 2011). Collectively, the data suggested that Ang2-specific Tie2 translocation and inhibition of cell motility occurs early after Ang2 stimulation, and that VEGF and the ECM environment also modulate Ang2-induced functions.…”

Section: Substrate-bound Ang2 Mediates Weak Cell Adhesion and Spreadingmentioning

confidence: 88%

Ligand oligomerization state controls Tie2 receptor trafficking and Angiopoietin-2 ligand-specific responses

Pietilä

Nätynki

Tammela

et al. 2012

Journal of Cell Science

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SummaryAngiopoietin 1 (Ang1) is an activating ligand for the endothelial receptor tyrosine kinase Tie2, whereas Ang2 acts as a contextdependent agonist or antagonist that has a destabilizing effect on the vasculature. The molecular mechanisms responsible for the versatile functions of Ang2 are poorly understood. We show here that Ang2, but not Ang1, induces Tie2 translocation to the specific cell-matrix contact sites located at the distal end of focal adhesions. The Ang2-specific Tie2 translocation was associated with distinct Tie2 activation and downstream signals which differed from those of Ang1, and led to impaired cell motility and weak cell-matrix adhesion. We demonstrate that the different oligomeric or multimeric forms of the angiopoietins induce distinct patterns of Tie2 trafficking; the lower oligomerization state of native Ang2 was crucial for the Ang2-specific Tie2 redistribution, whereas multimeric structures of Ang1 and Ang2 induced similar responses. The Ang2-specific Tie2 trafficking to cell-matrix contacts was also dependent on the cell substratum, a2b1-integrin-containing cell-matrix adhesion sites and intact microtubules. Our data indicate that the different subcellular trafficking of Tie2-Ang2 and Tie2-Ang1 complexes generates ligand-specific responses in the angiopoietin-Tie signaling pathway, including modulation of cell-matrix interactions.

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Section: Substrate-bound Ang2 Mediates Weak Cell Adhesion and Spreadingmentioning

confidence: 88%

Ligand oligomerization state controls Tie2 receptor trafficking and Angiopoietin-2 ligand-specific responses

Pietilä

Nätynki

Tammela

et al. 2012

Journal of Cell Science

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“…Low vWF activity perhaps indicates ongoing endothelial perturbation in patients with more severe PAH, portending worse survival. vWF has also been shown to be a potent angiogenesis inhibitor (46). It is possible that in the presence of low vWF activity there is increased angiogenesis leading to a more aggressive PAH phenotype and worse survival.…”

Section: Original Researchmentioning

confidence: 99%

Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension

Al‐Naamani

Palevsky²,

Lederer

et al. 2016

Annals ATS

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Rationale: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction.Objectives: The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH. Methods:We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, b-thromboglobulin, and thromboxane B 2 ) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed. Measurements and Main Results:Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B 2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance. Conclusions:In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation.Clinical trial registered with www.clinicaltrials.gov (NCT00384865).

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“…Therefore, it is quite possible that other pathways leading to Ang-2 gene expression could be involved. Most interesting is the novel observation that in vitro loss of vWF can induce Ang-2 release from EC resulting in sprouting angiogenesis (23). Whether a selective decrease of the HMWMs of vWF as seen in CF LVAD subjects can cause a similar effect is unknown and warrants investigation.…”

Section: Mechanism Of Ang-2 Productionmentioning

confidence: 99%