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1.
J Cell Sci ; 128(12): 2236-48, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25956888

ABSTRACT

Autocrine VEGF is necessary for endothelial survival, although the cellular mechanisms supporting this function are unknown. Here, we show that--even after full differentiation and maturation--continuous expression of VEGF by endothelial cells is needed to sustain vascular integrity and cellular viability. Depletion of VEGF from the endothelium results in mitochondria fragmentation and suppression of glucose metabolism, leading to increased autophagy that contributes to cell death. Gene-expression profiling showed that endothelial VEGF contributes to the regulation of cell cycle and mitochondrial gene clusters, as well as several--but not all--targets of the transcription factor FOXO1. Indeed, VEGF-deficient endothelium in vitro and in vivo showed increased levels of FOXO1 protein in the nucleus and cytoplasm. Silencing of FOXO1 in VEGF-depleted cells reversed expression profiles of several of the gene clusters that were de-regulated in VEGF knockdown, and rescued both cell death and autophagy phenotypes. Our data suggest that endothelial VEGF maintains vascular homeostasis through regulation of FOXO1 levels, thereby ensuring physiological metabolism and endothelial cell survival.


Subject(s)
Apoptosis , Autocrine Communication , Autophagy , Biomarkers/metabolism , Endothelium, Vascular/pathology , Forkhead Transcription Factors/metabolism , Mitochondria/pathology , Vascular Endothelial Growth Factor A/physiology , Animals , Blotting, Western , Cell Differentiation , Cell Proliferation , Cells, Cultured , Endothelium, Vascular/metabolism , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Gene Expression Profiling , Humans , Hypoxia/physiopathology , Mice , Mice, Knockout , Mitochondria/metabolism , Phosphorylation , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction
2.
Arterioscler Thromb Vasc Biol ; 35(1): 30-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25278287

ABSTRACT

The past 5 years have witnessed a significant expansion in our understanding of vascular endothelial growth factor (VEGF) signaling. In particular, the process of canonical activation of VEGF receptor tyrosine kinases by homodimeric VEGF molecules has now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. Although heterodimer receptors were described 2 decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (noncanonical) has been identified through galectin and gremlin binding and upon rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and noncanonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications.


Subject(s)
Receptors, Vascular Endothelial Growth Factor/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism , Angiogenesis Modulating Agents/pharmacology , Animals , Autocrine Communication , Galectins/metabolism , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Ligands , Neovascularization, Pathologic , Neovascularization, Physiologic , Protein Conformation , Protein Multimerization , Receptors, Vascular Endothelial Growth Factor/drug effects , Signal Transduction/drug effects
3.
Cell ; 159(3): 473-4, 2014 Oct 23.
Article in English | MEDLINE | ID: mdl-25417099

ABSTRACT

The distribution and patterning of blood vessels is controlled by vascular endothelial growth factor (VEGF), which is precisely regulated throughout its life cycle. Okabe et al. show that VEGF is titrated away from the endothelium by adjacent neurons via endocytosis, regulating density and trajectory of blood vessels.


Subject(s)
Neovascularization, Physiologic , Neurons/metabolism , Retina/growth & development , Vascular Endothelial Growth Factor A/metabolism , Animals
4.
Cell ; 156(3): 549-62, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24485460

ABSTRACT

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.


Subject(s)
Capillary Permeability , Endothelium, Vascular/metabolism , Uterus/metabolism , Animals , Endometrium/metabolism , Female , Gene Expression Regulation , Humans , Mice , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
5.
Curr Opin Hematol ; 19(3): 176-83, 2012 May.
Article in English | MEDLINE | ID: mdl-22406825

ABSTRACT

PURPOSE OF REVIEW: This review offers a concise summary of the most recent experimental advances in vascular development using the mouse as a model organism. RECENT FINDINGS: Recent mouse studies have revealed a spread of phenotypic diversity between endothelia of distinct developmental origins and organs. For example, expression of unique transcription factors distinguishes hemogenic from nonhemogenic endothelium within the same vessel. Vasculature of the brain is particularly susceptible to endothelial malformations due to combinatorial germline and somatic mutations; surprisingly these mutations can afflict the endothelium by either cell autonomous or paracrine effects. Mutant mice have been used to understand how multiple signaling pathways integrate and refine cellular responses. In particular, we learned how VEGFR3 regulates Notch signaling and EphrinB2 coordinates VEGFR2 responses. The regulation of Prox1 by miR181 highlighted the contribution of microRNAs in the induction of lymphatic endothelium. Information gained on heterotypic interactions has further clarified the influence of blood vessels on the morphogenesis of parenchyma and contributed to our understanding of organ-specific endothelial differentiation. Finally, mouse models have uncovered endothelial cell polarity as a keystone for successful vascular lumenization. SUMMARY: Our understanding of the process of vascular development has gained significant refinement in the last two years and has clarified the origin of several disorders rooted in development.


Subject(s)
Blood Vessels/growth & development , Cell Differentiation/physiology , Intercellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Models, Animal , Animals , Blood Vessels/embryology , Blood Vessels/metabolism , Cell Communication/physiology , Endothelium, Vascular/physiology , Hematopoiesis/physiology , Mice , Receptors, Notch/metabolism , Signal Transduction/physiology , Vascular Diseases/genetics , Vascular Diseases/physiopathology
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