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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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Proposed model for the molecular reorganization of endothelial intercellular junctions in the absence of β-catenin. (A) In the presence of β-catenin (β), α-catenin (α) is normally expressed at cell–cell junctions and connects VE-cadherin/β-catenin or VE-cadherin/plakoglobin (PG) complex to actin cytoskeleton. (B) In the absence of β-catenin, the decrease in α-catenin, accompanied by increase in desmoplakin (DP), may lead to a shift from α-catenin and actin based junctions to desmoplakin and vimentin-based complexus adhaerentes.
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fig11: Proposed model for the molecular reorganization of endothelial intercellular junctions in the absence of β-catenin. (A) In the presence of β-catenin (β), α-catenin (α) is normally expressed at cell–cell junctions and connects VE-cadherin/β-catenin or VE-cadherin/plakoglobin (PG) complex to actin cytoskeleton. (B) In the absence of β-catenin, the decrease in α-catenin, accompanied by increase in desmoplakin (DP), may lead to a shift from α-catenin and actin based junctions to desmoplakin and vimentin-based complexus adhaerentes.

Mentions: In contrast to epithelial cells, endothelial cells do not have desmosomes, neither do they express desmogleins or desmocollins (Franke et al., 1988). However, they have complexus adhaerentes (Schmelz et al., 1994) formed by VE-cadherin linked to plakoglobin or p0071 (Calkins et al., 2002), which through the binding to desmoplakin, mediate the anchorage to vimentin (Valiron et al., 1996; Kowalczyk et al., 1998; Gallicano et al., 2001). Although desmoplakin and vimentin are present in other types of endothelium (Valiron et al., 1996; Kowalczyk et al., 1998), complexus adhaerentes are preferentially observed in lymphatics, where junctions are relatively weak, allowing a dynamic passage of cells and solutes (Schmelz et al., 1994; Stacker et al., 2002). We speculate that in the absence of β-catenin, plakoglobin may bind to α-catenin only to a limited extent while increasing its interaction with desmoplakin (see the scheme in Fig. 11). According to this model, we found that both the level of desmoplakin and its distribution at intercellular junctions were significantly increased in β-catenin −/− cells. These molecular changes lead to an overall decrease of the number of strong, actin-based adherens junctions to weak, more dynamic vimentin based complexus adhaerentes. Consistently, it was recently reported that β-catenin is reduced in lymphatic as compared with vascular endothelium (Petrova et al., 2002).


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)

Proposed model for the molecular reorganization of endothelial intercellular junctions in the absence of β-catenin. (A) In the presence of β-catenin (β), α-catenin (α) is normally expressed at cell–cell junctions and connects VE-cadherin/β-catenin or VE-cadherin/plakoglobin (PG) complex to actin cytoskeleton. (B) In the absence of β-catenin, the decrease in α-catenin, accompanied by increase in desmoplakin (DP), may lead to a shift from α-catenin and actin based junctions to desmoplakin and vimentin-based complexus adhaerentes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172846&req=5

fig11: Proposed model for the molecular reorganization of endothelial intercellular junctions in the absence of β-catenin. (A) In the presence of β-catenin (β), α-catenin (α) is normally expressed at cell–cell junctions and connects VE-cadherin/β-catenin or VE-cadherin/plakoglobin (PG) complex to actin cytoskeleton. (B) In the absence of β-catenin, the decrease in α-catenin, accompanied by increase in desmoplakin (DP), may lead to a shift from α-catenin and actin based junctions to desmoplakin and vimentin-based complexus adhaerentes.
Mentions: In contrast to epithelial cells, endothelial cells do not have desmosomes, neither do they express desmogleins or desmocollins (Franke et al., 1988). However, they have complexus adhaerentes (Schmelz et al., 1994) formed by VE-cadherin linked to plakoglobin or p0071 (Calkins et al., 2002), which through the binding to desmoplakin, mediate the anchorage to vimentin (Valiron et al., 1996; Kowalczyk et al., 1998; Gallicano et al., 2001). Although desmoplakin and vimentin are present in other types of endothelium (Valiron et al., 1996; Kowalczyk et al., 1998), complexus adhaerentes are preferentially observed in lymphatics, where junctions are relatively weak, allowing a dynamic passage of cells and solutes (Schmelz et al., 1994; Stacker et al., 2002). We speculate that in the absence of β-catenin, plakoglobin may bind to α-catenin only to a limited extent while increasing its interaction with desmoplakin (see the scheme in Fig. 11). According to this model, we found that both the level of desmoplakin and its distribution at intercellular junctions were significantly increased in β-catenin −/− cells. These molecular changes lead to an overall decrease of the number of strong, actin-based adherens junctions to weak, more dynamic vimentin based complexus adhaerentes. Consistently, it was recently reported that β-catenin is reduced in lymphatic as compared with vascular endothelium (Petrova et al., 2002).

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