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Actin-tethered junctional complexes in angiogenesis and lymphangiogenesis in association with vascular endothelial growth factor.

Zankov DP, Ogita H - Biomed Res Int (2015)

Bottom Line: Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes.Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms.We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Shiga, Otsu 520-2192, Japan.

ABSTRACT
Vasculature is present in all tissues and therefore is indispensable for development, biology, and pathology of multicellular organisms. Endothelial cells guarantee proper function of the vessels and are the original component in angiogenesis. Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes. Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis. Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms. Afadin mediates the pathways of vascular endothelial growth factor- (VEGF-) and sphingosine 1-phosphate-triggered angiogenesis and is essential for embryonic development of lymph vessels in mice. We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

No MeSH data available.


Related in: MedlinePlus

Sequence of regulatory steps leading to damage of lymph endothelial barrier in afadin cKO mouse embryos. In the absence of afadin-mediated inhibition of RhoA activity, actin stress fibers are formed. Thick actin filaments alter the cell shape, dislocate VE-cadherin from cell membrane, compromise adherent junctions, and damage lymph EC barrier. This results in generalized edema and embryonic death.
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fig3: Sequence of regulatory steps leading to damage of lymph endothelial barrier in afadin cKO mouse embryos. In the absence of afadin-mediated inhibition of RhoA activity, actin stress fibers are formed. Thick actin filaments alter the cell shape, dislocate VE-cadherin from cell membrane, compromise adherent junctions, and damage lymph EC barrier. This results in generalized edema and embryonic death.

Mentions: The mice with EC-targeted deletion of afadin [43] were born in a significantly reduced ratio (3.6% versus 25% expected), showing that afadin is also important for embryonic AG. That observation became the topic of our investigation [57], in which we found that most of the endothelial afadin cKO mouse embryos died at embryonic day (E) 16.5. Until E13.5, no detectable dissimilarities between cKO and control embryos could be observed, but at E14.5–E16.5, cKO mice developed diffuse subcutaneous edema and dot-like skin hemorrhages. Series of immunofluorescence experiments demonstrated that lymphatic vessels in the skin of afadin cKO embryos were largely dilated and that lymphatic endothelium exhibited defect in VE-cadherin staining but preserved ability to differentiate and proliferate. To investigate afadin-induced dysfunction of lymphatic endothelium, human dermal blood and lymphatic microvascular ECs (BMVECs and LMVECs, resp.) were used as a model. Knockdown of afadin in LMVECs triggered cell-shape alteration, disorganization of cell-cell contacts, reduction of VE-cadherin staining, and formation of thick F-actin fibers at the cells periphery. All of these effects were not produced in BMVECs. Afadin-associated F-actin/VE-cadherin rearrangements in LMVECs depended on RhoA activity: GTP-bound (active) RhoA was increased in afadin-knockdown LMVECs and dominant negative RhoA mutant rescued the phenotype in LVMECs. Thus, afadin stabilizes adherens junctions/VE-cadherin by suppressing RhoA activity and stress fibers formation to maintain EC barrier in embryonic lymphatic vessels (Figure 3). Actin fibers organization is reported as condition that defines the localization of VE-cadherin in cell junctions. Actin depolymerization or hyperpolymerization has been shown to decrease VE-cadherin in ECs and compromise endothelial barrier [58]. Contraction of cortical actin-myosin cytoskeleton in ECs stimulated by Rho GTPase has similar effect [59]. Actin bundles in ECs formed after cAMP/Epac/Rap1 stimulation anchor VE-cadherin and strengthen cell-cell adhesions, the effect that results in reduction of endothelial layer permeability [60, 61].


Actin-tethered junctional complexes in angiogenesis and lymphangiogenesis in association with vascular endothelial growth factor.

Zankov DP, Ogita H - Biomed Res Int (2015)

Sequence of regulatory steps leading to damage of lymph endothelial barrier in afadin cKO mouse embryos. In the absence of afadin-mediated inhibition of RhoA activity, actin stress fibers are formed. Thick actin filaments alter the cell shape, dislocate VE-cadherin from cell membrane, compromise adherent junctions, and damage lymph EC barrier. This results in generalized edema and embryonic death.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4389985&req=5

fig3: Sequence of regulatory steps leading to damage of lymph endothelial barrier in afadin cKO mouse embryos. In the absence of afadin-mediated inhibition of RhoA activity, actin stress fibers are formed. Thick actin filaments alter the cell shape, dislocate VE-cadherin from cell membrane, compromise adherent junctions, and damage lymph EC barrier. This results in generalized edema and embryonic death.
Mentions: The mice with EC-targeted deletion of afadin [43] were born in a significantly reduced ratio (3.6% versus 25% expected), showing that afadin is also important for embryonic AG. That observation became the topic of our investigation [57], in which we found that most of the endothelial afadin cKO mouse embryos died at embryonic day (E) 16.5. Until E13.5, no detectable dissimilarities between cKO and control embryos could be observed, but at E14.5–E16.5, cKO mice developed diffuse subcutaneous edema and dot-like skin hemorrhages. Series of immunofluorescence experiments demonstrated that lymphatic vessels in the skin of afadin cKO embryos were largely dilated and that lymphatic endothelium exhibited defect in VE-cadherin staining but preserved ability to differentiate and proliferate. To investigate afadin-induced dysfunction of lymphatic endothelium, human dermal blood and lymphatic microvascular ECs (BMVECs and LMVECs, resp.) were used as a model. Knockdown of afadin in LMVECs triggered cell-shape alteration, disorganization of cell-cell contacts, reduction of VE-cadherin staining, and formation of thick F-actin fibers at the cells periphery. All of these effects were not produced in BMVECs. Afadin-associated F-actin/VE-cadherin rearrangements in LMVECs depended on RhoA activity: GTP-bound (active) RhoA was increased in afadin-knockdown LMVECs and dominant negative RhoA mutant rescued the phenotype in LVMECs. Thus, afadin stabilizes adherens junctions/VE-cadherin by suppressing RhoA activity and stress fibers formation to maintain EC barrier in embryonic lymphatic vessels (Figure 3). Actin fibers organization is reported as condition that defines the localization of VE-cadherin in cell junctions. Actin depolymerization or hyperpolymerization has been shown to decrease VE-cadherin in ECs and compromise endothelial barrier [58]. Contraction of cortical actin-myosin cytoskeleton in ECs stimulated by Rho GTPase has similar effect [59]. Actin bundles in ECs formed after cAMP/Epac/Rap1 stimulation anchor VE-cadherin and strengthen cell-cell adhesions, the effect that results in reduction of endothelial layer permeability [60, 61].

Bottom Line: Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes.Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms.We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Shiga, Otsu 520-2192, Japan.

ABSTRACT
Vasculature is present in all tissues and therefore is indispensable for development, biology, and pathology of multicellular organisms. Endothelial cells guarantee proper function of the vessels and are the original component in angiogenesis. Morphogenesis of the vascular system utilizes processes like cell adhesion, motility, proliferation, and survival that are closely related to the dynamics of actin filaments and actin-tethered adhesion complexes. Here we review involvement of actin cytoskeleton-associated junctional molecules of endothelial cells in angiogenesis and lymphangiogenesis. Particularly, we focus on F-actin binding protein afadin, an adaptor protein involved in broad range of signaling mechanisms. Afadin mediates the pathways of vascular endothelial growth factor- (VEGF-) and sphingosine 1-phosphate-triggered angiogenesis and is essential for embryonic development of lymph vessels in mice. We propose that targeting actin-tethered junctional molecules, including afadin, may present a new approach to angiogenic therapy that in combination with today used medications like VEGF inhibitors will benefit against development of pathological angiogenesis.

No MeSH data available.


Related in: MedlinePlus