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The conditional inactivation of the beta-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility.

Cattelino A, Liebner S, Gallini R, Zanetti A, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R, Dejana E - J. Cell Biol. (2003)

Bottom Line: We found that early phases of vasculogenesis and angiogenesis were not affected in mutant embryos; however, vascular patterning in the head, vitelline, umbilical vessels, and the placenta was altered.These changes paralleled a decrease in cell-cell adhesion strength and an increase in paracellular permeability.We conclude that in vivo, the absence of beta-catenin significantly reduces the capacity of endothelial cells to maintain intercellular contacts.

View Article: PubMed Central - PubMed

Affiliation: FIRC Institute of Molecular Oncology, 16-20139, Milan, Italy.

ABSTRACT
Using the Cre/loxP system we conditionally inactivated beta-catenin in endothelial cells. We found that early phases of vasculogenesis and angiogenesis were not affected in mutant embryos; however, vascular patterning in the head, vitelline, umbilical vessels, and the placenta was altered. In addition, in many regions, the vascular lumen was irregular with the formation of lacunae at bifurcations, vessels were frequently hemorrhagic, and fluid extravasation in the pericardial cavity was observed. Cultured beta-catenin -/- endothelial cells showed a different organization of intercellular junctions with a decrease in alpha-catenin in favor of desmoplakin and marked changes in actin cytoskeleton. These changes paralleled a decrease in cell-cell adhesion strength and an increase in paracellular permeability. We conclude that in vivo, the absence of beta-catenin significantly reduces the capacity of endothelial cells to maintain intercellular contacts. This may become more marked when the vessels are exposed to high or turbulent flow, such as at bifurcations or in the beating heart, leading to fluid leakage or hemorrhages.

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Morphological differences and junctional organization in control and β-catenin −/− endothelial cells in culture. A represents β-catenin flox/flox del (control) endothelial cells, whereas B represents the same cells after infection with an adeno vector expressing Cre recombinase (β-catenin flox del/flox del, or −/−). In C, E, and G, endothelial cells cultured from control embryos are shown, whereas D, F, and H show endothelial cells from β-catenin −/− embryos. Although control endothelial cells exhibit classical cobblestone morphology (A and C), β-catenin −/− cells are more elongated and have a fibroblastoid/mesenchymal morphology (B and D). Phalloidin staining shows more elongated and thinner bundles of actin filaments in β-catenin −/− cells (F), as compared with controls (E). β-Catenin staining is undetectable at intercellular contacts of −/− cells (compare G and H), whereas ZO-1 (I and J) and VE-cadherin (K and L) are correctly organized at intercellular junctions.
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fig6: Morphological differences and junctional organization in control and β-catenin −/− endothelial cells in culture. A represents β-catenin flox/flox del (control) endothelial cells, whereas B represents the same cells after infection with an adeno vector expressing Cre recombinase (β-catenin flox del/flox del, or −/−). In C, E, and G, endothelial cells cultured from control embryos are shown, whereas D, F, and H show endothelial cells from β-catenin −/− embryos. Although control endothelial cells exhibit classical cobblestone morphology (A and C), β-catenin −/− cells are more elongated and have a fibroblastoid/mesenchymal morphology (B and D). Phalloidin staining shows more elongated and thinner bundles of actin filaments in β-catenin −/− cells (F), as compared with controls (E). β-Catenin staining is undetectable at intercellular contacts of −/− cells (compare G and H), whereas ZO-1 (I and J) and VE-cadherin (K and L) are correctly organized at intercellular junctions.

Mentions: To study whether the morphological and functional defects observed in β-catenin −/− endothelial cells in vivo were independent from their tissue context, we isolated and cultured endothelial cells from mutant and wild-type embryos. β-Catenin −/− endothelial cells presented all endothelial markers analyzed (Fig. 6–8; unpublished data), but cell morphology was significantly different. β-Catenin −/− cells were more elongated as compared with control cells (Fig. 6, C and D), and presented thinner and longer bundles of actin filaments, with sensibly less organized anchorage sites at the periphery of the cell (Fig. 6, E and F).


The conditional inactivation of the beta-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility.

Cattelino A, Liebner S, Gallini R, Zanetti A, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R, Dejana E - J. Cell Biol. (2003)

Morphological differences and junctional organization in control and β-catenin −/− endothelial cells in culture. A represents β-catenin flox/flox del (control) endothelial cells, whereas B represents the same cells after infection with an adeno vector expressing Cre recombinase (β-catenin flox del/flox del, or −/−). In C, E, and G, endothelial cells cultured from control embryos are shown, whereas D, F, and H show endothelial cells from β-catenin −/− embryos. Although control endothelial cells exhibit classical cobblestone morphology (A and C), β-catenin −/− cells are more elongated and have a fibroblastoid/mesenchymal morphology (B and D). Phalloidin staining shows more elongated and thinner bundles of actin filaments in β-catenin −/− cells (F), as compared with controls (E). β-Catenin staining is undetectable at intercellular contacts of −/− cells (compare G and H), whereas ZO-1 (I and J) and VE-cadherin (K and L) are correctly organized at intercellular junctions.
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Related In: Results  -  Collection

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fig6: Morphological differences and junctional organization in control and β-catenin −/− endothelial cells in culture. A represents β-catenin flox/flox del (control) endothelial cells, whereas B represents the same cells after infection with an adeno vector expressing Cre recombinase (β-catenin flox del/flox del, or −/−). In C, E, and G, endothelial cells cultured from control embryos are shown, whereas D, F, and H show endothelial cells from β-catenin −/− embryos. Although control endothelial cells exhibit classical cobblestone morphology (A and C), β-catenin −/− cells are more elongated and have a fibroblastoid/mesenchymal morphology (B and D). Phalloidin staining shows more elongated and thinner bundles of actin filaments in β-catenin −/− cells (F), as compared with controls (E). β-Catenin staining is undetectable at intercellular contacts of −/− cells (compare G and H), whereas ZO-1 (I and J) and VE-cadherin (K and L) are correctly organized at intercellular junctions.
Mentions: To study whether the morphological and functional defects observed in β-catenin −/− endothelial cells in vivo were independent from their tissue context, we isolated and cultured endothelial cells from mutant and wild-type embryos. β-Catenin −/− endothelial cells presented all endothelial markers analyzed (Fig. 6–8; unpublished data), but cell morphology was significantly different. β-Catenin −/− cells were more elongated as compared with control cells (Fig. 6, C and D), and presented thinner and longer bundles of actin filaments, with sensibly less organized anchorage sites at the periphery of the cell (Fig. 6, E and F).

Bottom Line: We found that early phases of vasculogenesis and angiogenesis were not affected in mutant embryos; however, vascular patterning in the head, vitelline, umbilical vessels, and the placenta was altered.These changes paralleled a decrease in cell-cell adhesion strength and an increase in paracellular permeability.We conclude that in vivo, the absence of beta-catenin significantly reduces the capacity of endothelial cells to maintain intercellular contacts.

View Article: PubMed Central - PubMed

Affiliation: FIRC Institute of Molecular Oncology, 16-20139, Milan, Italy.

ABSTRACT
Using the Cre/loxP system we conditionally inactivated beta-catenin in endothelial cells. We found that early phases of vasculogenesis and angiogenesis were not affected in mutant embryos; however, vascular patterning in the head, vitelline, umbilical vessels, and the placenta was altered. In addition, in many regions, the vascular lumen was irregular with the formation of lacunae at bifurcations, vessels were frequently hemorrhagic, and fluid extravasation in the pericardial cavity was observed. Cultured beta-catenin -/- endothelial cells showed a different organization of intercellular junctions with a decrease in alpha-catenin in favor of desmoplakin and marked changes in actin cytoskeleton. These changes paralleled a decrease in cell-cell adhesion strength and an increase in paracellular permeability. We conclude that in vivo, the absence of beta-catenin significantly reduces the capacity of endothelial cells to maintain intercellular contacts. This may become more marked when the vessels are exposed to high or turbulent flow, such as at bifurcations or in the beating heart, leading to fluid leakage or hemorrhages.

Show MeSH
Related in: MedlinePlus