Molecular Basis for Endothelial Lumen Formation and Tubulogenesis During Vasculogenesis and Angiogenic Sprouting

Davis, George E.; Stratman, Amber N.; Sacharidou, Anastasia; Koh, Wonshill

doi:10.1016/b978-0-12-386041-5.00003-0

Cited by 168 publications

(209 citation statements)

References 220 publications

(639 reference statements)

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“…S2A). Endothelial lumen formation is a crucial aspect of endothelial morphogenesis and tubulogenesis (Davis et al, 2011), and MT1-MMP is required for both successful lumen formation and endothelial cell sprouting into collagen matrices (Chun et al, 2004;Stratman et al, 2009;Sacharidou et al, 2010). S1P has been shown to stimulate phosphorylation of MT1-MMP at Y573 (Nyalendo et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Dave

Abbey

Duran

et al. 2016

Journal of Cell Science

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During angiogenesis, endothelial cells must coordinate matrix proteolysis with migration. Here, we tested whether the focal adhesion scaffold protein Hic-5 (also known as TGFB1I1) regulated endothelial sprouting in three dimensions. Hic-5 silencing reduced endothelial sprouting and lumen formation, and sprouting defects were rescued by the return of Hic-5 expression. Pro-angiogenic factors enhanced colocalization and complex formation between membrane type-1 matrix metalloproteinase (MT1-MMP, also known as MMP14) and Hic-5, but not between paxillin and MT1-MMP. The LIM2 and LIM3 domains of Hic-5 were necessary and sufficient for Hic-5 to form a complex with MT1-MMP. The degree of interaction between MT1-MMP and Hic-5 and the localization of the complex within detergent-resistant membrane fractions were enhanced during endothelial sprouting, and Hic-5 depletion lowered the surface levels of MT1-MMP. In addition, we observed that loss of Hic-5 partially reduced complex formation between MT1-MMP and focal adhesion kinase (FAK, also known as PTK2), suggesting that Hic-5 bridges MT1-MMP and FAK. Finally, Hic-5 LIM2-LIM3 deletion mutants reduced sprout initiation. Hic-5, MT1-MMP and FAK colocalized in angiogenic vessels during porcine pregnancy, supporting that this complex assembles during angiogenesis in vivo. Collectively, Hic-5 appears to enhance complex formation between MT1-MMP and FAK in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility.

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Section: Resultsmentioning

confidence: 99%

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Dave

Abbey

Duran

et al. 2016

Journal of Cell Science

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“…Our laboratory and others have previously reported intracellular vacuoles contributing to lumen formation in vitro and in vivo (Bayless and Davis, 2002;Davis et al, 2011;Folkman and Haudenschild, 1980a;Kamei et al, 2006;Koh et al, 2009;Sacharidou et al, 2012). However, other recent work has highlighted the importance of cellular rearrangements and multicellular/extracellular lumenization (Wacker and Gerhardt, 2011), and the existence of intracellular vacuoles or nascent lumenal compartments has been questioned.…”

Section: Intracellular Vacuoles Within Individual Ecs Are Likely To Cmentioning

confidence: 95%

Single cell analysis of endothelial morphogenesis in vivo

Castranova

Pham

et al. 2015

Development

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Vessel formation has been extensively studied at the tissue level, but the difficulty in imaging the endothelium with cellular resolution has hampered study of the morphogenesis and behavior of endothelial cells (ECs) in vivo. We are using endothelial-specific transgenes and high-resolution imaging to examine single ECs in zebrafish. By generating mosaics with transgenes that simultaneously mark endothelial nuclei and membranes we are able to definitively identify and study the morphology and behavior of individual ECs during vessel sprouting and lumen formation. Using these methods, we show that developing trunk vessels are composed of ECs of varying morphology, and that single-cell analysis can be used to quantitate alterations in morphology and dynamics in ECs that are defective in proper guidance and patterning. Finally, we use singlecell analysis of intersegmental vessels undergoing lumen formation to demonstrate the coexistence of seamless transcellular lumens and single or multicellular enclosed lumens with autocellular or intercellular junctions, suggesting that heterogeneous mechanisms contribute to vascular lumen formation in vivo. The tools that we have developed for single EC analysis should facilitate further rigorous qualitative and quantitative analysis of EC morphology and behavior in vivo.

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“…Over a decade ago, studies showed that it was essential for in vitro EC lumen formation (Bayless and Davis, 2002;Davis et al, 2011). Cdc42 was then shown to be similarly required for lumen formation in epithelial systems, both in vitro (Bray et al, 2011;Bryant et al, 2010;Martin-Belmonte and Mostov, 2007) and in vivo (Kesavan et al, 2009;Melendez et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

Barry

Meadows

et al. 2015

Development

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The Rho family of small GTPases has been shown to be required in endothelial cells (ECs) during blood vessel formation. However, the underlying cellular events controlled by different GTPases remain unclear. Here, we assess the cellular mechanisms by which Cdc42 regulates mammalian vascular morphogenesis and maintenance. In vivo deletion of Cdc42 in embryonic ECs (Cdc42 Tie2KO ) results in blocked lumen formation and endothelial tearing, leading to lethality of mutant embryos by E9-10 due to failed blood circulation. Similarly, inducible deletion of Cdc42 (Cdc42 Cad5KO ) at mid-gestation blocks angiogenic tubulogenesis. By contrast, deletion of Cdc42 in postnatal retinal vessels leads to aberrant vascular remodeling and sprouting, as well as markedly reduced filopodia formation. We find that Cdc42 is essential for organization of EC adhesion, as its loss results in disorganized cell-cell junctions and reduced focal adhesions. Endothelial polarity is also rapidly lost upon Cdc42 deletion, as seen by failed localization of apical podocalyxin (PODXL) and basal actin. We link observed failures to a defect in F-actin organization, both in vitro and in vivo, which secondarily impairs EC adhesion and polarity. We also identify Cdc42 effectors Pak2/4 and N-WASP, as well as the actomyosin machinery, to be crucial for EC actin organization. This work supports the notion of Cdc42 as a central regulator of the cellular machinery in ECs that drives blood vessel formation.

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Molecular Basis for Endothelial Lumen Formation and Tubulogenesis During Vasculogenesis and Angiogenic Sprouting

Cited by 168 publications

References 220 publications

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Single cell analysis of endothelial morphogenesis in vivo

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

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