Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

Vandersmissen, Ine; Craps, Sander; Depypere, Maarten; Coppiello, Giulia; Gastel, Nick van; Maes, Frederik; Carmeliet, Geert; Schrooten, Jan; Jones, Elizabeth A. V.; Umans, Lieve; Devlieger, Roland; Gheysens, Olivier; Zwijsen, An; Aranguren, Xabier L.; Luttun, Aernout

doi:10.1083/jcb.201502003

Cited by 15 publications

(26 citation statements)

References 68 publications

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“…A downstream effector and upstream mediator within the BMP-signalling cascade active in ECs is the transcription factor Muscle Segment Homeobox 1 (MSX1). It is involved in BMP-mediated EndMT in endocardial ECs during atrioventricular valve formation in vivo 323334. However, it remains unclear whether MSX1 induction alone is sufficient to direct EndMT of ECs in culture.…”

Section: Resultsmentioning

confidence: 99%

A new strategy to measure intercellular adhesion forces in mature cell-cell contacts

Sancho

Vandersmissen

Craps

et al. 2017

Sci Rep

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Intercellular adhesion plays a major role in tissue development and homeostasis. Yet, technologies to measure mature cell-cell contacts are not available. We introduce a methodology based on fluidic probe force microscopy to assess cell-cell adhesion forces after formation of mature intercellular contacts in cell monolayers. With this method we quantify that L929 fibroblasts exhibit negligible cell-cell adhesion in monolayers whereas human endothelial cells from the umbilical artery (HUAECs) exert strong intercellular adhesion forces per cell. We use a new in vitro model based on the overexpression of Muscle Segment Homeobox 1 (MSX1) to induce Endothelial-to-Mesenchymal Transition (EndMT), a process involved in cardiovascular development and disease. We reveal how intercellular adhesion forces in monolayer decrease significantly at an early stage of EndMT and we show that cells undergo stiffening and flattening at this stage. This new biomechanical insight complements and expands the established standard biomolecular analyses. Our study thus introduces a novel tool for the assessment of mature intercellular adhesion forces in a physiological setting that will be of relevance to biological processes in developmental biology, tissue regeneration and diseases like cancer and fibrosis.

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Section: Resultsmentioning

confidence: 99%

A new strategy to measure intercellular adhesion forces in mature cell-cell contacts

Sancho

Vandersmissen

Craps

et al. 2017

Sci Rep

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“…As arteriogenesis, one of the two forms of vessel growth after birth, represents an important adaptive response to haemodynamic changes or chronic hypoxia (Boroujerdi et al , ; Vandersmissen et al , ), we evaluated whether propranolol impairs arteriogenic remodelling in tumours, by performing immunostaining of endothelial cells for vWF and pericytes for α‐SMA. Pericyte‐positive vessels were defined as vWF‐positive structures associated with at least one α‐SMA‐positive cell.…”

Section: Resultsmentioning

confidence: 99%

Biphasic effects of propranolol on tumour growth in B16F10 melanoma‐bearing mice

Maccari¹,

Buoncervello²,

Rampin

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEPropranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity. EXPERIMENTAL APPROACHEffects of increasing doses of propranolol (10, 20, 30 and 40 mg·kg À1 ·day À1 ) on tumour growth were studied in B16F10 melanoma-bearing mice. Histological and biochemical analyses were used to assess propranolol effects on angiogenesis and cancer cell proliferation. Systemic vascular resistance (SVR) was evaluated by measuring cardiac output and arterial BP. KEY RESULTSIn vitro analyses revealed that B16F10 cells expressed β-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor the β-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasic dose-response curve. Low doses (10 and 20 mg·kg À1 ·day À1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We also found that high-dose propranolol stimulates tumour arteriogenesis whereas no effect on angiogenesis was observed at any dose. Based on these data and considering that propranolol is a vasoactive drug, we hypothesized that it causes systemic vasoconstriction or vasodilation depending on the dose and thus alters tumour perfusion and growth. Consistent with this hypothesis, we found that propranolol has a biphasic effect on SVR with low and high doses producing vasoconstriction and vasodilation respectively. CONCLUSIONS AND IMPLICATIONSPropranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and antimelanoma activity.Abbreviations α-SMA, α-smooth muscle actin; CO, cardiac output; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; HR, heart rate; IB4, isolectin B4; SV, stroke volume; SVR, systemic vascular resistance; vWF, Von Willebrand Factor Introduction β-Adrenoceptors are a family of G-protein coupled receptors comprising three subtypes, β 1 , β 2 and β 3 , which act by activating a Gs protein. These receptors play a role in the regulation of peripheral vascular resistance, heart function and airway reactivity, as well as a variety of metabolic and CNS functions. β-Adrenoceptors also regulate cellular processes involved in cancer and angiogenesis and are the molecular target of β-blockers, a class of drugs which inhibits the interaction of catecholamines with β-adrenoceptors.In vitro studies indicate that propranolol, the prototype of β-blockers, reduces melanoma cell proliferation in human and murine melanoma cell lines (Dal Monte et al., 2013;Moretti et al., 2013;Calvani et al., 2015;Wrobel and Le Gal, 2015). Furthermore, the systemic administration of propranolol slows down tumour development in immunodeficient mice transplanted with human melanoma cells (Wrobel and Le Gal, 2015) and inhibits the effects of stress on the growth and metast...

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“…After incubation, the unbound THP-1 cells were removed by washing with PBS and the attached THP-1 cells on the endothelial cells monolayer were fixed with 4% PFA for 10 min. Ten pictures per well were taken at a 100× magnification, and the number of attached THP-1 cells per field of view was analyzed by ImageJ software, as previously described [17]. …”

Section: Methodsmentioning

confidence: 99%

The Essential Role of Pin1 via NF-κB Signaling in Vascular Inflammation and Atherosclerosis in ApoE−/− Mice

Liu

Jiang

et al. 2017

IJMS

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Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide. However, the mechanisms that underlie the inflammatory process are not completely understood. Prolyl-isomerase-1 (Pin1), as a unique peptidyl-prolyl isomerase, plays an important role in inflammation and endothelial dysfunction. Herein, we investigate whether Pin1 regulates vascular inflammation and atherosclerosis, and clarify its mechanisms in these processes. ApoE −/− mice were randomly given either juglone (0.3, 1 mg/kg, two times per week) or vehicle i.p. for 4 weeks. Compared with ApoE −/− mice, treatment by juglone resulted not only in markedly attenuated macrophage infiltration and atherosclerotic lesion area in a lipid-independent manner, but also in decreased expression of Pin1, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and NF-κB activity in aorta. Then, EA.hy926 cells were pretreated with juglone (6 µmol/L), Pin1 siRNA, NF-κB inhibitor, or vehicle prior to exposure to ox-LDL (50 µg/mL). It was observed that treatment with juglone or Pin1 siRNA suppressed expression of VCAM-1 in oxLDL-incubated EA.hy926 cells and decreased THP-1 cell adhesion to oxLDL-stimulated endothelial cells through the NF-κB signal pathway. Our findings indicate that Pin1 plays a vital role on the development of vascular inflammation and atherosclerosis.

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Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

Cited by 15 publications

References 68 publications

A new strategy to measure intercellular adhesion forces in mature cell-cell contacts

A new strategy to measure intercellular adhesion forces in mature cell-cell contacts

Biphasic effects of propranolol on tumour growth in B16F10 melanoma‐bearing mice

The Essential Role of Pin1 via NF-κB Signaling in Vascular Inflammation and Atherosclerosis in ApoE−/− Mice

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