Elevated glucose inhibits VEGF-A–mediated endocardial cushion formation

Enciso, Josephine; Gratzinger, Dita; Camenisch, Todd D.; Canosa, Sandra; Pinter, Emese; Madri, Joseph A.

doi:10.1083/jcb.200209014

Cited by 90 publications

(83 citation statements)

References 53 publications

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“…Thus, MMP2 clearly has the potential to modulate an important stage of cardiac morphogenesis-the interval when endocardial endothelial cells transform and invade the cardiac jelly ECM (Song et al, 2000). In fact, murine endocardial epithelial-to-mesenchymal transformation is positively correlated with levels of MMP2 expression (Enciso et al, 2003). The expression patterns in Figures 2 and 3 suggest that MMP2 is not required for the transformation event itself, but rather, for mesenchymal cell invasion.…”

Section: Mmp2 Is Active During Endocardial Mesenchyme Invasionmentioning

confidence: 70%

Matrix Metalloproteinase 2-Integrin αvβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

Rupp

Visconti

Czirók

et al. 2008

MBoC

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Cellular invasive behavior through three-dimensional collagen gels was analyzed using computational time-lapse imaging. A subpopulation of endocardial cells, derived from explanted quail cardiac cushions, undergoes an epithelialto-mesenchymal transition and invades the substance of the collagen gels when placed in culture. In contrast, other endocardial cells remain epithelial and move over the gel surface. Here, we show that integrin ␣v␤3 and matrix metalloproteinase (MMP)2 are present and active in cushion mesenchymal tissue. More importantly, functional assays show that mesenchymal invasive behavior is dependent on MMP2 activity and integrin ␣v␤3 binding. Inhibitors of MMP enzymatic activity and molecules that prevent integrin ␣v␤3 binding to MMP2, via its hemopexin domain, result in significantly reduced cellular protrusive activity and invasive behavior. Computational analyses show diminished intensity and persistence time of motility in treated invasive mesenchymal cells, but no reduction in motility of the epithelial-like cells moving over the gel surface. Thus, quantitative time-lapse data show that mesenchymal cell invasive behavior, but not epithelial cell locomotion over the gel surface, is partially regulated by the MMP2-integrin interactions. INTRODUCTIONCell motility within a three-dimensional (3D) tissue space, often termed invasion, is a dynamic process involved in a host of morphological and pathological events (Harris, 1987). Extracellular matrix (ECM) fibers provide mechanical support for tissue integrity/deformations, act as a scaffold for cell motility, and act as a repository of growth factors and latent enzymes (McCarthy and Turley, 1993;Damsky et al., 1997;Friedl and Brocker, 2000;Davis and Senger, 2005). Cell invasion is often coupled to local ECM degradation (Ellis and Murphy, 2001). In an extreme case, structures termed invadopodia have been observed on the surface of invasive tumor cells. These structures are cellular protrusions that contain surface-bound, externally facing proteases (Chen, 1989;Mueller and Chen, 1991;Monsky et al., 1993Monsky et al., , 1994Kelly et al., 1994).During normal embryonic development extracellular matrix protease activity is important for successful epithelialto-mesenchymal transformations (EMT) that accompany neural crest, sclerotome, and renal tubular cell delamination (Cheng and Lovett, 2003;Song et al., 2000;Duong and Erickson, 2004). During epithelial-to-mesenchymal transformations ECM proteolysis may not only remove a physical barrier, but also expose cell receptor sites and regulatory molecules sequestered in the ECM. Similar proteolytic events are recapitulated during angiogenesis and tubulogenesis in vitro (Bayless and Davis, 2003;Fisher et al., 2006). When deprived of specific proteolytic mechanisms, some cell types change their motility strategy and move through the ECM by means of amoeboid behavior (Wolf et al., 2003).Degradation of the ECM occurs by a number of secreted proteinases. One family, the matrix metalloproteinases (MMPs), is compose...

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Section: Mmp2 Is Active During Endocardial Mesenchyme Invasionmentioning

confidence: 70%

Matrix Metalloproteinase 2-Integrin αvβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

Rupp

Visconti

Czirók

et al. 2008

MBoC

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“…New studies show that myocardial VEGF expression is repressed in the nascent cushion and that this allows endocardial endothelial cells to initiate their differentiation into mesenchymal cells (Chang et al, 2004). The role of VEGF in EMT is likely to be complex, and depend on spatial and temporal regulation given that, in two other studies of mouse embryonic valve development, VEGF was found to be a positive regulator of EMT (Enciso et al, 2003;Hallaq et al, 2004). In our laboratory, we showed a functional link between VEGF and the transcription factor NFATc1 in human post-natal valve endothelial cells (HPVEC) (Johnson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish

Lee

Cope

Ackermann

et al. 2005

Developmental Dynamics

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“…Serial sections through the entire AV cushion were examined and the section with the most positive cells was used for quantitation. Atrio-ventricular canal endocardial cushion explant culture Atrio-ventricular (AV) explant cultures were performed as described (Enciso et al, 2003). Briefly, the AV canal and ventricle (AV explant) from E10.5 mice with >28 somites were placed on rat tail type I collagen (Fisher, Collaborative Biomedical) gels which were hydrated for a minimum of 1 hour with 100 µl of Medium 199 supplemented with 1% FBS, 100 u/ml penicillin, 100 µg/ml streptomycin, and 0.1% each of insulin, transferrin, and selenium (GIBCO BRL).…”

Section: Immunohistochemistrymentioning

confidence: 99%

A null mutation ofHhexresults in abnormal cardiac development,defective vasculogenesis and elevated Vegfa levels

et al. 2004

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The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex–/– mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2)hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex–/– mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex–/– AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.

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Elevated glucose inhibits VEGF-A–mediated endocardial cushion formation

Cited by 90 publications

References 53 publications

Matrix Metalloproteinase 2-Integrin αvβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

Matrix Metalloproteinase 2-Integrin αvβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish

A null mutation ofHhexresults in abnormal cardiac development,defective vasculogenesis and elevated Vegfa levels

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