The power of VEGF (vascular endothelial growth factor) family molecules

Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors (VEGFRs) are key regulators of both angiogenesis and neurogenesis. The current issue of CMLS discusses recent literature and work implementing these signals in nervous system development, maintenance and disease pathology.     

Vascular endothelial growth factor signaling in acute myeloid leukemia

This review is designed to provide an overview of the current literature concerning vascular endothelial growth factor signaling (VEGF) in acute myeloid leukemia (AML). Aberrant VEGF signaling operates in the bone marrow of AML patients and is related to a poor prognosis. The altered signaling pathway demonstrated to interfere in several autocrine and paracrine signaling pathways. VEGF signaling promotes autocrine AML blast cell proliferation, survival, and chemotherapy resistance. In addition, VEGF signaling can mediate paracrine vascular endothelial cell-controlled angiogenesis in AML. Both effects presumably explain the association of high VEGF levels and poor therapeutic outcome. More recently, researches focusing on bone marrow stem cell niches demonstrate a role for VEGF signaling in the preservation of several cell types within these niches. The bone marrow niches are proposed to be a protective microenvironment for AML cells that could be responsible for relapses in AML patients. This implies the need of sophisticated VEGF-targeted therapeutics in AML therapy strategies. This review highlights our current understanding of aberrant VEGF signaling in AML, appoints the interference of VEGF signaling in the AML-associated microenvironment, and reflects the novelty of current VEGF-targeted therapeutics used in clinical trails for the treatment of AML.     

Spatially defined oxygen gradients and vascular endothelial growth factor expression in an engineered 3D cell model

Tissue hypoxia results in rapid angiogenesis in vivo, triggered by angiogenic proteins, including vascular endothelial growth factor (VEGF). Current views of tissue viability are founded on whether ‘deeper-lying’ cells receive sufficient nutrients and oxygen for normal activity and ultimately survival. For intact tissues, levels of such essential nutrients are governed by micro-vascular perfusion. However, there have been few effective quantitatively defined 3D models, which enable testing of the interplay or interdependence of matrix and cell density, and path diffusion on oxygen consumption in vitro. As a result, concepts on cell vulnerability to low oxygen levels, together with the nature of cellular responses are ill defined. The present study has adapted a novel, optical fibre-based system for in situ, real-time oxygen monitoring within three-dimensionally-spiralled cellular collagen constructs, which were then unfurled to enable quantitative, spatial measurements of VEGF production in different parts of the same construct exposed to different oxygen levels. A VEGF response was elicited by cells exposed to low oxygen levels (20 mmHg), primarily within the construct core. Received 3 August 2007; received after revision 24 October 2007; accepted 29 October 2007 An erratum to this article is available at .     

Vascular endothelial growth factors (VEGFs) and stroke

Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair, and the effects of transplanted stem cells in experimental stroke. Most of these actions involve VEGF-A and the VEGFR-2 receptor, but VEGF-B, placental growth factor, and VEGFR-1 have been implicated in some cases as well. VEGF signaling pathways represent important potential targets for the acute and chronic treatment of stroke.     

N-acetylglucosaminyltransferase V modifies the signaling pathway of epidermal growth factor receptor

Transfection of sense cDNA of N-acetylglucosamyltransferase V (GnTV-S) into human H7721 hepatocarcinoma cells resulted in an increase in the N-acetylglucosamine1,6mannose1,3- branch (GnT-V product) on the N-glycans of epidermal growth factor (EGF) receptor (EGFR), and promotion of its EGF binding and tyrosine autophosphorylation, but showed little effect on the expression of EGFR protein. The phosphorylation at T308, S473 and tyrosine residue(s) and the activity of protein kinase B (Akt/PKB) as well as the phosphorylation of p42/44 mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) before and after EGF stimulation were concomitantly increased. Conversely, in the antisense GnT-V (GnTV-AS)-transfected H7721 cells, all the results were the reverse of those with GnTV-S-transfected cells. After the cells were treated with 1-deoxymannojirimycin, an inhibitor of N-glycan processing at high mannose, or antibody against the extracellular glycan domain of EGFR, the differences in PKB activity, p42/44 MAPK and MEK phosphorylation among GnTV-S-, GnTV-AS- and mock-transfected cells were significantly attenuated. These findings indicate that the altered expression of GnT-V will change the glycan structure and function of EGFR, which may modify downstream signal transduction.Received 24 March 2004; received after revision 1 May 2004; accepted 25 May 2004     

Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt

The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However, the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression, we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt. Received 23 November 2005; received after revision 10 January 2006; accepted 9 February 2006     

The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling

Increasing evidence links blood coagulation proteins with the regulation of acute and chronic inflammatory disease. Of particular interest are vitamin K-dependent proteases, which are generated as a hemostatic response to vascular injury, but can also initiate signal transduction via interactions with vascular receptors. The endothelial cell protein C receptor (EPCR) is a multi-ligand vitamin K-dependent protein receptor for zymogen and activated forms of plasma protein C and factor VII. Although the physiological role of the EPCR-FVII(a) interaction is not well-understood, protein C binding to EPCR facilitates rapid generation of APC in response to excessive thrombin generation, and is a central requirement for the multiple signal-transduction cascades initiated by APC on both vascular endothelial and innate immune cells. Exciting recent studies have highlighted the emerging role of EPCR in modulating the cytoprotective properties of APC in a number of diverse inflammatory disorders. In this review, we describe the structure–function relationships, signal transduction pathways, and cellular interactions that enable EPCR to modulate the anticoagulant and anti-inflammatory properties of its vitamin K-dependent protein ligands, and examine the relevance of EPCR to both thrombotic and inflammation-associated disease.     

Something old,something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation

The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R “borrows” components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment.     

Assessment of superoxide-mediated release of vascular-inhibitory factor(s) from endothelial cells by using a two-bath system

Release of a vascular-inhibitory factor from endothelial cells (EC), different from endothelium-derived relaxant factor (EDRF), was identified through use of a two-bath system. This two-bath system precluded the effects of oxygen-free radicals that appear when electrical field stimulation (EFS) is directly imposed on detector muscle.     

Assessment of superoxide-mediated release of vascular-inhibitory factor(s) from endothelial cells by using a two-bath system

Summary Release of a vascular-inhibitory factor from endothelial cells (EC), different from endothelium-derived relaxant factor (EDRF), was identified through use of a two-bath system. This two-bath system precluded the effects of oxygen-free radicals that appear when electrical field stimulation (EFS) is directly imposed on detector muscle.     

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.     

In vitro study of cellular affinity to various protein supports suited for vascular prosthesis]

We compare the affinity of different cellular samples with regard to variosu artificial materials by organotypic culture method. We use a technique which allows at once, to obtain the cells and to measure their migration on the artificial surface. The results show a high variation of the cellular affinity from one sample to another.     

Anin vivo bioassay for TSH-releasing factor (TRF)

Résumé Une méthode de bioétalonnagein vivo pour la mise en évidence de l'activité TRF (TSH-releasing factor) est décrite. Cette méthode est basée sur la mesure de la radíoactivité totale du sang chez le rat normal (non-hypophysectomisé) prétraité avec I¹³¹ et une dose liminaire del-thyroxine. La spécificité de ce test est discutée; Vasopressine, ocytocine,-MSH,-MSH sont inactifs dans ce test.     

The role of the insulin-like growth factor (IGF) axis in osteogenic and odontogenic differentiation

The insulin-like growth factor (IGF) axis is a multicomponent molecular network which has important biological functions in the development and maintenance of differentiated tissue function(s). One of the most important functions of the IGF axis is the control of skeletal tissue metabolism by the finely tuned regulation of the process of osteogenesis. To achieve this, the IGF axis controls the activity of several cell types—osteoprogenitor cells, osteoblasts, osteocytes and osteoclasts to achieve the co-ordinated development of appropriate hard tissue structure and associated matrix deposition. In addition, there is an increasing awareness that the IGF axis also plays a role in the process of odontogenesis (tooth formation). In this review, we highlight some of the key findings in both of these areas. A further understanding of the role of the IGF axis in hard tissue biology may contribute to tissue regeneration strategies in cases of skeletal tissue trauma.     

Epidermal growth factor (EGF) accelerates the maturation of fetal mouse intestinal mucosa in utero

Summary Pregnant Swiss ICR mice were injected i.p. with 0.5 g of epidermal growth factor (EGF) per g b. wt at 15, 16 and 17 days of gestation and fetuses were removed at 18 days of gestation. EGF treatment had no effect on the weight of the fetuses and on the length of the small intestine. No modification of the protein and DNA contents was noted. However brush border alkaline phosphatase and trehalase activities were significantly increased as well as endoplasmic reticulum membrane-bound glucose-6-phosphatase.Supported by grant MA-6069 from the Medical Research Council of Canada. Dr D. Ménard is a chercheur boursier du Fonds de la recherche en santé du Québec