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Vascular endothelial growth factor promotes cardiomyocyte differentiation of embryonic stem cells. 2006

Yu Chen, and Ivo Amende, and Thomas G Hampton, and Yinke Yang, and Qingen Ke, and Jiang-Yong Min, and Yong-Fu Xiao, and James P Morgan
Harvard Medical School, Boston, MA 02215, USA.

Embryonic stem cells (ESCs) overexpressing the vascular endothelial growth factor (VEGF) improve cardiac function in mouse models of myocardial ischemia and infarction by mechanisms that are poorly understood. Here we studied the effects of VEGF on cardiomyocyte differentiation of mouse ESCs in vitro. We used flow cytometry to determine the expression of alpha-myosin heavy chain (alpha-MHC), cardiac troponin I (cTn-I), and Nkx2.5 in differentiated ESCs. VEGF (20 ng/ml) significantly enhanced alpha-MHC, cTn-I, and Nkx2.5 expression in differentiated ESCs. Western blot analysis confirmed these findings. We found that VEGF receptor FMS-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1) expression increased during ESC differentiation. Antibodies against Flk-1 totally blocked and against Flt-1 partially blocked VEGF-induced NKx2.5-positive-stained cells. The ERK inhibitor PD-098059 abolished VEGF-induced cardiomyocyte differentiation of ESCs. Our results suggest that VEGF promotes cardiomyocyte differentiation predominantly by ERK-mediated Flk-1 activation and, to a lesser extent, by Flt-1 activation. These findings may be of significance for stem cell and growth factor therapies to regenerate failing cardiomyocytes.

UI MeSH Term Description Entries
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005419 Flavonoids A group of phenyl benzopyrans named for having structures like FLAVONES. 2-Phenyl-Benzopyran,2-Phenyl-Chromene,Bioflavonoid,Bioflavonoids,Flavonoid,2-Phenyl-Benzopyrans,2-Phenyl-Chromenes,2 Phenyl Benzopyran,2 Phenyl Benzopyrans,2 Phenyl Chromene,2 Phenyl Chromenes
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D000072576 Homeobox Protein Nkx-2.5 A homeobox-containing transcription factor that functions in heart development. Mutations in the NKX2-5 gene are associated with ATRIAL SEPTAL DEFECTS and TETRALOGY OF FALLOT. Cardiac-Specific Homeobox Protein,Homeobox Protein Csx-Nkx2.5,Homeobox Transcription Factor Csx-Nkx2-5,NK2 Homeobox 5 Protein,Transcription Factor Nkx-2.5,Cardiac Specific Homeobox Protein,Csx-Nkx2.5, Homeobox Protein,Homeobox Protein Csx Nkx2.5,Homeobox Protein Nkx 2.5,Homeobox Protein, Cardiac-Specific,Homeobox Transcription Factor Csx Nkx2 5,Nkx-2.5, Homeobox Protein,Nkx-2.5, Transcription Factor,Transcription Factor Nkx 2.5
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D042461 Vascular Endothelial Growth Factor A The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as "tumor angiogenesis factor" and "vascular permeability factor". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced. Vascular Endothelial Growth Factor,Vascular Endothelial Growth Factor-A,GD-VEGF,Glioma-Derived Vascular Endothelial Cell Growth Factor,VEGF,VEGF-A,Vascular Permeability Factor,Vasculotropin,Glioma Derived Vascular Endothelial Cell Growth Factor,Permeability Factor, Vascular
D048049 Extracellular Signal-Regulated MAP Kinases A mitogen-activated protein kinase subfamily that is widely expressed and plays a role in regulation of MEIOSIS; MITOSIS; and post mitotic functions in differentiated cells. The extracellular signal regulated MAP kinases are regulated by a broad variety of CELL SURFACE RECEPTORS and can be activated by certain CARCINOGENS. ERK MAP Kinase,ERK MAP Kinases,Extracellular Signal-Regulated Kinase,Extracellular Signal-Regulated Kinases,Extracellular Signal-Regulated MAP Kinase,MAP Kinases, Extracellular Signal-Regulated,Extracellular Signal Regulated Kinase,Extracellular Signal Regulated Kinases,Extracellular Signal Regulated MAP Kinase,Extracellular Signal Regulated MAP Kinases,Kinase, ERK MAP,Kinase, Extracellular Signal-Regulated,Kinases, Extracellular Signal-Regulated,MAP Kinase, ERK,MAP Kinases, Extracellular Signal Regulated,Signal-Regulated Kinase, Extracellular
D048670 MAP Kinase Kinase 4 A mitogen-activated protein kinase kinase with specificity for JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES and the RETINOID X RECEPTORS. It takes part in a SIGNAL TRANSDUCTION pathway that is activated in response to cellular stress. JN Kinase Kinase,JNK Kinase,JNK-Activating Protein Kinase,JNKK1 Protein Kinase,Jun Amino-Terminal Kinase Kinase,MEK4 Protein Kinase,Mitogen-Activated Protein Kinase Kinase 4,SAP Kinase Kinase 1,SAP Kinase-Extracellular Signal-Regulated Kinase Kinase 1,SAPK-ERK Kinase 1,SEK1 Protein Kinase,Stress-Activated Protein Kinase Kinase 1,JNK Activating Protein Kinase,Jun Amino Terminal Kinase Kinase,Kinase, JNKK1 Protein,Mitogen Activated Protein Kinase Kinase 4,Protein Kinase, JNK-Activating,Protein Kinase, JNKK1,Protein Kinase, MEK4,Protein Kinase, SEK1,SAP Kinase Extracellular Signal Regulated Kinase Kinase 1,SAPK ERK Kinase 1,Stress Activated Protein Kinase Kinase 1

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