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1.
Arterioscler Thromb Vasc Biol ; 37(9): 1710-1721, 2017 09.
Article in English | MEDLINE | ID: mdl-28729362

ABSTRACT

OBJECTIVE: Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown. APPROACH AND RESULTS: By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In Sema3f-null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbs1 in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. Sema3f-/- mice placentas are also highly anemic and abnormally vascularized. CONCLUSIONS: Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs1 in visceral yolk sac epithelial cells.


Subject(s)
Epithelial Cells/metabolism , Membrane Proteins/metabolism , Neovascularization, Physiologic , Nerve Tissue Proteins/metabolism , Placenta/blood supply , Yolk Sac/blood supply , Animals , Cell Line, Tumor , Embryonal Carcinoma Stem Cells/metabolism , Endothelial Cells/metabolism , Female , Gene Expression Regulation, Developmental , Genotype , Gestational Age , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , MicroRNAs/metabolism , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Phenotype , Phosphorylation , Pregnancy , Proteolysis , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction , Thrombospondin 1/genetics , Thrombospondin 1/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
2.
Cell Adh Migr ; 10(6): 641-651, 2016 11.
Article in English | MEDLINE | ID: mdl-27439112

ABSTRACT

Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors.


Subject(s)
Cardiovascular System/embryology , Cardiovascular System/metabolism , Semaphorins/metabolism , Animals , Humans , Models, Biological , Mutation/genetics , Phenotype , Signal Transduction
3.
J Clin Invest ; 122(5): 1832-48, 2012 May.
Article in English | MEDLINE | ID: mdl-22484816

ABSTRACT

Cancer development, progression, and metastasis are highly dependent on angiogenesis. The use of antiangiogenic drugs has been proposed as a novel strategy to interfere with tumor growth, but cancer cells respond by developing strategies to escape these treatments. In particular, animal models show that antiangiogenic drugs currently used in clinical settings reduce tumor tissue oxygenation and trigger molecular events that foster cancer resistance to therapy. Here, we show that semaphorin 3A (Sema3A) expression overcomes the proinvasive and prometastatic resistance observed upon angiogenesis reduction by the small-molecule tyrosine inhibitor sunitinib in both pancreatic neuroendocrine tumors (PNETs) in RIP-Tag2 mice and cervical carcinomas in HPV16/E2 mice. By improving cancer tissue oxygenation and extending the normalization window, Sema3A counteracted sunitinib-induced activation of HIF-1α, Met tyrosine kinase receptor, epithelial-mesenchymal transition (EMT), and other hypoxia-dependent signaling pathways. Sema3A also reduced tumor hypoxia and halted cancer dissemination induced by DC101, a specific inhibitor of the VEGF pathway. As a result, reexpressing Sema3A in cancer cells converts metastatic PNETs and cervical carcinomas into benign lesions. We therefore suggest that this strategy could be developed to safely harnesses the therapeutic potential of the antiangiogenic treatment.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Indoles/therapeutic use , Liver Neoplasms/secondary , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Pyrroles/therapeutic use , Semaphorin-3A/genetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Hypoxia/drug effects , Combined Modality Therapy , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Female , Genetic Therapy , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Indoles/pharmacology , Lymphatic Metastasis , Mice , Mice, Transgenic , NF-kappa B/metabolism , Neoplasm Invasiveness , Neovascularization, Physiologic , Neuroendocrine Tumors/blood supply , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/therapy , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/therapy , Pericytes/pathology , Proto-Oncogene Proteins c-met/metabolism , Pyrroles/pharmacology , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Semaphorin-3A/biosynthesis , Sunitinib , Tumor Burden , Uterine Cervical Neoplasms/blood supply , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/therapy , Uterine Cervical Neoplasms/virology
4.
J Immunol ; 188(8): 4081-92, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22442441

ABSTRACT

The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6C(high) inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A-stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries.


Subject(s)
Macrophages, Peritoneal/immunology , Neovascularization, Physiologic , Semaphorins/physiology , Vascular Endothelial Growth Factor A/immunology , Animals , Cell Movement , Chemokines/biosynthesis , Chemokines/immunology , Chick Embryo , Chorioallantoic Membrane/blood supply , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelial Cells/pathology , Humans , Intracellular Signaling Peptides and Proteins , Lipopolysaccharides/pharmacology , Macrophage Activation , Macrophages, Peritoneal/pathology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Myocardium/pathology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Peritonitis/immunology , Peritonitis/metabolism , Peritonitis/pathology , Reperfusion Injury/immunology , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Semaphorins/pharmacology , Signal Transduction , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
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