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1.
J Biochem Mol Toxicol ; 34(11): e22572, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32633013

ABSTRACT

Angiogenic factor with G patch and FHA domains 1 (AGGF1) has strong proangiogenic effects on embryonic vascular development and angiogenesis in disease; however, its role in retinopathy has not been elucidated. Retinopathy of prematurity is a serious retinal disorder of premature infants, which is caused by the arrest of immature retinal vascular growth under hyperoxia. This study aims to investigate the effects of AGGF1 on retinal vascular endothelial cells under hyperoxia and the association with autophagy by using rhesus macaque choroid-retinal endothelial (RF/6A) cells. Western blot analysis and immunofluorescence staining were used to detect the expression of AGGF1 in RF/6A cells. Cell Counting Kit-8, flow cytometry, and transwell and matrigel assays were applied to detect the vitality, apoptosis, migration, and tube formation of RF/6A cells, respectively. Western blot analysis was then used to detect the expression of autophagy markers LC3 and Beclin-1, and mCherry-GFP-LC3 adenovirus was used to detect autophagy flux in RF/6A cells. Under hyperoxia, the expression of AGGF1 in RF/6A cells decreased compared with the control. Cell vitality, migration, and tube formation decreased, and apoptosis of RF/6A cells increased under hyperoxia, and these effects of hyperoxia were attenuated by AGGF1. The protein expressions of LC3 and Beclin-1 increased in RF/6A cells and autophagy flux enhanced under hyperoxia. AGGF1 reduced the expression of LC3 and Beclin-1 as well as the autophagy flux stimulated by hyperoxia. The results clearly showed that exogenous AGGF1 can protect retinal vascular endothelial cells and promote angiogenesis under hyperoxia, in which the expression of AGGF1 was inhibited. Inhibition of autophagy by AGGF1 may be one of the mechanisms involved.


Subject(s)
Angiogenic Proteins/physiology , Autophagy/drug effects , Endothelium, Vascular/drug effects , Hyperoxia/metabolism , Retinal Vessels/drug effects , Animals , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Humans , Retinal Vessels/cytology , Retinal Vessels/metabolism
2.
Mol Neurobiol ; 57(5): 2461-2478, 2020 May.
Article in English | MEDLINE | ID: mdl-32152825

ABSTRACT

Angiogenesis is the growth of new capillaries from the preexisting blood vessels. Glioblastoma (GBM) tumors are highly vascularized tumors, and glioma growth depends on the formation of new blood vessels. Angiogenesis is a complex process involving proliferation, migration, and differentiation of vascular endothelial cells (ECs) under the stimulation of specific signals. It is controlled by the balance between its promoting and inhibiting factors. Various angiogenic factors and genes have been identified that stimulate glioma angiogenesis. Therefore, attention has been directed to anti-angiogenesis therapy in which glioma proliferation is inhibited by inhibiting the formation of new tumor vessels using angiogenesis inhibitory factors and drugs. Here, in this review, we highlight and summarize the various molecular mediators that regulate GBM angiogenesis with focus on recent clinical research on the potential of exploiting angiogenic pathways as a strategy in the treatment of GBM patients.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Brain Neoplasms/blood supply , Glioblastoma/blood supply , Neovascularization, Pathologic/physiopathology , Adult , Angiogenesis Inhibitors/pharmacology , Angiogenic Proteins/antagonists & inhibitors , Angiogenic Proteins/physiology , Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cell Differentiation , Cell Hypoxia , Clinical Trials as Topic , Glioblastoma/drug therapy , Glioblastoma/pathology , Humans , Intercellular Signaling Peptides and Proteins/physiology , Matrix Metalloproteinases/physiology , Molecular Targeted Therapy , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/physiology , Neoplastic Stem Cells/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/prevention & control , Neovascularization, Physiologic/physiology , Tumor Microenvironment , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/physiology
3.
Curr Hypertens Rep ; 21(9): 69, 2019 07 24.
Article in English | MEDLINE | ID: mdl-31342170

ABSTRACT

PURPOSE OF REVIEW: This review provides a comprehensive insight into the angiogenic profile of hypertensive and normotensive pregnancies compromised by HIV infection. Furthermore, we evaluate the economic implementation of the sFlt-1/PlGF ratio and review the reports on therapeutic apheresis in limiting sFlt-1 production. RECENT FINDINGS: In preeclampsia, an increased expression of sFlt-1 triggers angiogenic imbalance. Women of African ancestry have high levels of angiogenic factors than other racial groups. The sFlt-1/PlGF ratio shows promise in the early assessment of preeclampsia, while sFlt-1 apheresis restores angiogenic imbalance. Studies suggest antiretroviral therapy does not impact the angiogenic shift in preeclampsia development. The angiogenic profile in pregnant women of different races influences preeclampsia development. Despite the opposing immune response in HIV infection and preeclampsia, the HIV tat protein strongly mimics vascular endothelial growth factor (VEGF); hence, it is plausible to assume that HIV infection may ameliorate the angiogenic imbalance in preeclampsia.


Subject(s)
HIV Infections/physiopathology , Pre-Eclampsia/physiopathology , Pregnancy Complications, Infectious/physiopathology , Angiogenic Proteins/blood , Angiogenic Proteins/physiology , Biomarkers/blood , Biomarkers/metabolism , Blood Component Removal , Female , HIV Infections/blood , HIV Infections/complications , Humans , Hypertension, Pregnancy-Induced/blood , Hypertension, Pregnancy-Induced/physiopathology , Hypertension, Pregnancy-Induced/therapy , Membrane Proteins/blood , Membrane Proteins/physiology , Neovascularization, Pathologic/blood , Neovascularization, Pathologic/physiopathology , Neovascularization, Physiologic/physiology , Pre-Eclampsia/blood , Pre-Eclampsia/therapy , Pregnancy , Pregnancy Complications, Infectious/blood , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/physiology , Vascular Endothelial Growth Factor Receptor-1/blood , Vascular Endothelial Growth Factor Receptor-1/physiology , tat Gene Products, Human Immunodeficiency Virus/blood , tat Gene Products, Human Immunodeficiency Virus/physiology
4.
Math Biosci ; 306: 32-48, 2018 12.
Article in English | MEDLINE | ID: mdl-30393207

ABSTRACT

We present a 2D mathematical model of tumor angiogenesis which is an extension of the 1D model originally presented in Levine et al. (2000) [1]. Our model is connected to that 1D model by some transmission and boundary conditions which carry certain cells, the endothelials, pericytes and macrophages from the vessel wall into the extra cellular matrix. In our extended model we also include a mechanism for the action of anti-angiogenic factors such as angiostatin. We present numerical simulations in which we obtain a very good "qualitative agreement" with the time of the onset of vascularization of tumors and with the fact that the capillary tip growth accelerates as it approaches the "tumor".


Subject(s)
Models, Biological , Neoplasms/blood supply , Neovascularization, Pathologic , Angiogenic Proteins/physiology , Angiostatins/physiology , Animals , Capillaries/pathology , Cell Movement , Computer Simulation , Extracellular Matrix/pathology , Extracellular Matrix/physiology , Humans , Mathematical Concepts , Neoplasms/pathology , Neoplasms/physiopathology , Tumor Microenvironment
5.
PLoS One ; 13(4): e0195779, 2018.
Article in English | MEDLINE | ID: mdl-29641565

ABSTRACT

Angiogenesis has been implicated in glomerular alterations in the early stage of diabetic nephropathy. We previously reported the renoprotective effects of vasohibin-1 (VASH1), which is a novel angiogenesis inhibitor derived from endothelial cells, on diabetic nephropathy progression. Vasohibin-2 (VASH2) was originally identified as a VASH1 homolog and possesses pro-angiogenic activity in contrast to VASH1. In addition, VASH2 was recently shown to promote epithelial-to-mesenchymal transition via enhanced transforming growth factor (TGF)-ß signaling in cancer cells. Herein, we investigated the pathogenic roles of VASH2 in diabetic nephropathy using VAHS2-deficient mice. The type 1 diabetes model was induced by intraperitoneal injections of streptozotocin in VASH2 homozygous knockout (VASH2LacZ/LacZ) or wild-type mice. These mice were euthanized 16 weeks after inducing hyperglycemia. Increased urine albumin excretion and creatinine clearance observed in diabetic wild-type mice were significantly prevented in diabetic VASH2-deficient mice. Accordingly, diabetes-induced increase in glomerular volume and reduction in glomerular slit-diaphragm density were significantly improved in VASH2 knockout mice. Increased glomerular endothelial area was also suppressed in VASH2-deficient mice, in association with inhibition of enhanced vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), but not VEGF level. Furthermore, glomerular accumulation of mesangial matrix, including type IV collagen, and increased expression of TGF-ß were improved in diabetic VASH2 knockout mice compared with diabetic wild-type mice. Based on the immunofluorescence findings, endogenous VASH2 localization in glomeruli was consistent with mesangial cells. Human mesangial cells (HMCs) were cultured under high glucose condition in in vitro experiments. Transfection of VASH2 small interfering RNA (siRNA) into the HMCs resulted in the suppression of type IV collagen production induced by high glucose compared with control siRNA. These results indicate that VASH2 may be involved in diabetes-induced glomerular alterations, particularly impaired filtration barrier and mesangial expansion. Therefore, VASH2 is likely to represent a promising therapeutic target for diabetic nephropathy.


Subject(s)
Angiogenic Proteins/physiology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 1/complications , Diabetic Nephropathies/prevention & control , Mesangial Cells/pathology , Neovascularization, Pathologic/prevention & control , Animals , Cells, Cultured , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/pathology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Humans , Male , Mesangial Cells/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/metabolism , Sequence Deletion , Vascular Endothelial Growth Factor Receptor-2/metabolism
6.
Actas Dermosifiliogr ; 108(6): 515-523, 2017.
Article in English, Spanish | MEDLINE | ID: mdl-28162227

ABSTRACT

Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological inflammation and tumor growth, which underlies a complex interplay of stimulating and inhibiting signals. Extracellular matrix, cells of innate and adaptive immunity and endothelial cells itself are a major source of angiogenic factors that activate or inhibit specific receptors and consequently influence intracellular signaling pathways. Most inflammatory and neoplastic diseases in dermatology are characterized by excessive angiogenesis, such as psoriasis, atopic dermatitis, as well as melanoma, non-melanoma skin cancer, but also benign vascular neoplasia. In this article we describe current knowledge of angiogenesis and its most relevant mechanisms in different dermatological disorders with particular emphasis on the angiogenic factors (vascular endothelial growth factor) and angiopoietins as a target of current and future directions of anti-angiogenic therapy.


Subject(s)
Neovascularization, Pathologic/etiology , Neovascularization, Physiologic , Skin Diseases/complications , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Angiogenic Proteins/physiology , Angiopoietins/antagonists & inhibitors , Angiopoietins/physiology , Drug Resistance, Neoplasm , Hemangioma/drug therapy , Hemangioma/physiopathology , Humans , Melanoma/complications , Melanoma/drug therapy , Melanoma/immunology , Melanoma/physiopathology , Molecular Targeted Therapy , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/physiology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/physiopathology , Psoriasis/drug therapy , Psoriasis/physiopathology , Receptor, TIE-2/antagonists & inhibitors , Receptor, TIE-2/physiology , Skin/blood supply , Skin Diseases/immunology , Skin Diseases/physiopathology , Skin Neoplasms/blood supply , Skin Neoplasms/complications , Skin Neoplasms/immunology , Skin Neoplasms/physiopathology
7.
J Leukoc Biol ; 100(5): 979-984, 2016 11.
Article in English | MEDLINE | ID: mdl-27406995

ABSTRACT

All animals heal, and the ability to heal is requisite for human health. One aspect of repair that has always been considered to be essential for adequate healing is the creation of a new vasculature via angiogenesis. As adult skin wounds heal, a period of rapid and robust capillary growth creates a vascular bed that has many fold more capillaries than does normal tissue. Over time, most of the newly formed capillaries regress, resulting in a final vascular density similar to that of normal skin. Certainly, new capillaries are necessary to bring nutrients, immune cells, and oxygen to healing wounds. Yet, the presumed functional importance of an overabundance of capillaries has recently been challenged, creating questions about whether excess capillary growth is truly necessary for healing. In particular, studies of wounds that heal exceptionally quickly and with less scar formation, such as those in fetal skin and oral mucosa, show that these tissues heal with a reduced angiogenic burst composed of more mature vessels that provide better oxygenation. The level of angiogenesis in wounds often correlates with the inflammatory response, largely because inflammatory cells produce an abundance of proangiogenic mediators. Both the selective reduction of inflammation and the selective reduction of angiogenesis have now been suggested as ways to improve scarring. These concepts link excessive inflammation and the production of a dense but poorly perfused capillary bed to inferior healing outcomes.


Subject(s)
Neovascularization, Physiologic/physiology , Wound Healing/physiology , Angiogenic Proteins/physiology , Animals , Capillaries/physiology , Cicatrix/physiopathology , Cicatrix/prevention & control , Endothelial Cells/physiology , Fetus/physiology , Fibrosis , Humans , Inflammation/physiopathology , Mouth Mucosa/blood supply , Mouth Mucosa/injuries , Mouth Mucosa/physiology , Pericytes/physiology , Prenatal Injuries/physiopathology , Regeneration/physiology , Skin/blood supply , Skin/injuries
8.
Future Cardiol ; 12(5): 585-99, 2016 09.
Article in English | MEDLINE | ID: mdl-27420190

ABSTRACT

Stem cells encode vascular endothelial growth factors (VEGFs), fibroblastic growth factors (FGFs), stem cell factor, stromal cell-derived factor, platelet growth factor and angiopoietin that can contribute to myocardial vascularization. VEGFs and FGFs are the most investigated growth factors. VEGFs regulate angiogenesis and vasculogenesis. FGFs stimulate vessel cell proliferation and differentiation and are regulators of endothelial cell migration, proliferation and survival. Clinical trials of VEGF or FGF for myocardial angiogenesis have produced disparate results. The efficacy of therapeutic angiogenesis can be improved by: (1) identifying the most optimal patients; (2) increased knowledge of angiogenic factor pharmacokinetics and proper dose; (3) prolonging contact of angiogenic factors with the myocardium; (4) increasing the efficiency of VEGF or FGF gene transduction; and (5) utilizing PET or MRI to measure myocardial perfusion and perfusion reserve.


Subject(s)
Fibroblast Growth Factors/therapeutic use , Myocardial Ischemia/therapy , Neovascularization, Physiologic , Vascular Endothelial Growth Factors/therapeutic use , Angiogenic Proteins/physiology , Cell Movement , Cell Proliferation/physiology , Endothelium, Vascular/cytology , Fibroblast Growth Factors/physiology , Humans , Vascular Endothelial Growth Factor A/physiology , Vascular Endothelial Growth Factor A/therapeutic use , Vascular Endothelial Growth Factors/physiology
9.
Carcinogenesis ; 36(11): 1429-39, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26424749

ABSTRACT

Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is involved in oral squamous cell carcinoma (OSCC) and glioblastoma progression. The NC11 domain of collagen XVI has been described previously with a strong implication in physiological processes. We detected the non-collagenous (NC) 11-domain in supernatants of OSCC cells after recombinant expression of full-length collagen XVI and in sera from OSCC patients and healthy individuals. Stable expression of NC11-green fluorescent protein (GFP) fusion protein in OSCC cells initiated proliferation control and block of anchorage-independent growth. Moreover, the NC11 domain triggered the generation of tubular-like net structures on laminin-rich matrix in contrast to mock-GFP control cells and cells expressing full-length collagen XVI. Taqman® quantitative PCR and diaminobenzidine staining in 2D- and 3D cell culture revealed a significantly increased gene and protein expression of VEGFR1, VEGFR2 and uPAR in recombinant NC11-GFP-expressing cells. Specific VEGF receptor inhibition with Axitinib or fetal calf serum heat inactivation prevented formation of tubular-like net structures. Accordantly, NC11-GFP coated culture slides led to an increase of focal adhesion contact formation and the upregulation of VEGFR1 and uPAR in three different non-transfected OSCC cell lines. In summary, we suggest that the NC11 domain of collagen XVI is a potential biomarker for OSCC and triggers vasculogenic mimicry via upregulation of endothelial receptors VEGFR1, VEGFR2 and uPAR in 2D- and 3D OSCC cell culture conditions.


Subject(s)
Carcinoma, Squamous Cell/blood supply , Collagen/physiology , Mouth Neoplasms/blood supply , Aged , Angiogenic Proteins/physiology , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Mouth Neoplasms/blood , Mouth Neoplasms/genetics , Neovascularization, Pathologic/metabolism , Protein Structure, Tertiary , Up-Regulation , Vascular Endothelial Growth Factor Receptor-1/genetics , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
10.
In Vivo ; 29(3): 309-17, 2015.
Article in English | MEDLINE | ID: mdl-25977376

ABSTRACT

Tumor cell vasculogenic mimicry refers to the formation of tumor cell-lined vessels that contribute to tumor neovascularization and nutrient and oxygen supply. These tumor cells express many endothelial and stem cell markers, resulting in them having a unique phenotype. This phenomenon is observed in a variety of neoplasms, such as glioblastomas and sarcomas, as well as breast, ovarian, liver and lung carcinomas. It is also evident in melanocytic lesions, regardless of their benign or malignant nature. The biochemical and molecular events that regulate vasculogenic mimicry provide opportunities for development of novel forms of tumor-targeted treatments. Furthermore, the presence of this process in a tumor might have prognostic implications.


Subject(s)
Melanoma/blood supply , Neovascularization, Pathologic/pathology , Angiogenic Proteins/physiology , Animals , Humans , Melanoma/metabolism , Melanoma/pathology , Neoplastic Stem Cells/physiology , Signal Transduction
12.
J Clin Invest ; 125(4): 1497-508, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25751059

ABSTRACT

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.


Subject(s)
Angiogenic Proteins/physiology , Guanylate Kinases/metabolism , Hippocampus/physiopathology , Learning Disabilities/genetics , Membrane Proteins/metabolism , Memory Disorders/genetics , Nerve Tissue Proteins/physiology , Neuronal Plasticity/physiology , Proto-Oncogene Proteins c-mdm2/physiology , Spatial Learning/physiology , Angiogenic Proteins/deficiency , Angiogenic Proteins/genetics , Animals , Brain/blood supply , Disks Large Homolog 4 Protein , Guanylate Kinases/deficiency , Guanylate Kinases/genetics , HEK293 Cells , Hippocampus/pathology , Humans , Learning Curve , Learning Disabilities/physiopathology , Long-Term Potentiation/physiology , Maze Learning/physiology , Membrane Proteins/deficiency , Membrane Proteins/genetics , Memory Disorders/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neuronal Plasticity/genetics , Neurons/ultrastructure , Protein Interaction Mapping , Protein Processing, Post-Translational , Protein Structure, Tertiary , Recombinant Fusion Proteins/metabolism , Synaptic Transmission/physiology , Ubiquitination
13.
Angiogenesis ; 18(2): 115-23, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25433512

ABSTRACT

Placental angiogenesis is critical to the success of human pregnancy. Angiogenesis is defined as the formation of new blood vessels from existing vasculature. Angiogenesis is necessary for the establishment of adequate placental perfusion, which is important for providing the optimum in utero environment to support fetal development. Defective placental angiogenesis is associated with several pregnancy complications, the most clinically important of which is preeclampsia; the multisystem disorder is characterized by maternal hypertension, proteinuria, and endothelial dysfunction. Here, we review our current understanding of several key angiogenic factors that are associated with placental angiogenesis. We also discuss their importance with respect to preeclampsia, where aberrant expression and release of these factors into the maternal circulation is thought to contribute to the pathogenesis and pathophysiology of preeclampsia.


Subject(s)
Angiogenic Proteins/physiology , Placenta/physiology , Pre-Eclampsia/etiology , Female , Humans , Pregnancy
14.
Exp Cell Res ; 332(2): 157-62, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25478999

ABSTRACT

Human mast cells (MCs) are a rich reservoir of neutral proteases, packed in large amounts in their granules and comprising a high fraction of all cellular proteins. Among these proteases, tryptase is involved in angiogenesis after its release from activated MC granules, as it has been demonstrated in different in vitro and in vivo assays. Moreover, tryptase-positive MCs increase in number and vascularization increases in a linear fashion in different solid and hematological tumors. This complex interplay between MCs and tumor angiogenesis have led to consider the therapeutic use of angiogenesis inhibitors, which specifically target the angiogenic activity of tryptase, such as gabexate mesilate and nafamostat mesilate, two inhibitors of trypsin-like serine proteases.


Subject(s)
Cytoplasmic Granules/enzymology , Mast Cells/enzymology , Tryptases/physiology , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Angiogenic Proteins/physiology , Animals , Humans , Molecular Targeted Therapy , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/enzymology , Neovascularization, Pathologic , Tryptases/antagonists & inhibitors
15.
J Endod ; 40(4 Suppl): S33-40, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24698691

ABSTRACT

Emerging understanding about interactions between stem cells, scaffolds, and morphogenic factors has accelerated translational research in the field of dental pulp tissue engineering. Dental pulp stem cells constitute a subpopulation of cells endowed with self-renewal and multipotency. Dental pulp stem cells seeded in biodegradable scaffolds and exposed to dentin-derived morphogenic factors give rise to a pulplike tissue capable of generating new dentin. Notably, dentin-derived proteins are sufficient to induce dental pulp stem cell differentiation into odontoblasts. Ongoing work is focused on developing ways of mobilizing dentin-derived proteins and disinfecting the root canal of necrotic teeth without compromising the morphogenic potential of these signaling molecules. On the other hand, dentin by itself does not appear to be capable of inducing endothelial differentiation of dental pulp stem cells despite the well-known presence of angiogenic factors in dentin. This is particularly relevant in the context of dental pulp tissue engineering in full root canals in which access to blood supply is limited to the apical foramina. To address this challenge, scientists are looking at ways to use the scaffold as a controlled-release device for angiogenic factors. The aim of this article was to present and discuss current strategies to functionalize injectable scaffolds and customize them for dental pulp tissue engineering. The long-term goal of this work is to develop stem cell-based therapies that enable the engineering of functional dental pulps capable of generating new tubular dentin in humans.


Subject(s)
Dental Pulp/cytology , Stem Cells/physiology , Tissue Engineering/methods , Tissue Scaffolds , Angiogenic Proteins/physiology , Cell Differentiation/physiology , Dentin/physiology , Humans , Multipotent Stem Cells/physiology , Odontoblasts/physiology , Proteins/physiology , Signal Transduction/physiology
16.
J Clin Invest ; 124(3): 878-87, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24590272

ABSTRACT

Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.


Subject(s)
Lymphangiogenesis/drug effects , Lymphatic Vessels/physiopathology , Angiogenic Proteins/physiology , Animals , Antineoplastic Agents/pharmacology , Humans , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/physiopathology , Signal Transduction
17.
J Clin Invest ; 124(3): 888-97, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24590273

ABSTRACT

The two vascular systems of our body are the blood and lymphatic vasculature. Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade. In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified. The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived. Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature.


Subject(s)
Lymphangiogenesis , Lymphatic Vessels/embryology , Angiogenic Proteins/physiology , Animals , Extracellular Matrix/physiology , Gene Expression Regulation, Developmental , Humans , Lymphatic Vessels/cytology , Lymphatic Vessels/physiology , Signal Transduction
18.
J Clin Invest ; 124(3): 936-42, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24590279

ABSTRACT

Lymphangiogenesis and lymphatic vessel remodeling are complex biological processes frequently observed during inflammation. Accumulating evidence indicates that inflammation-associated lymphangiogenesis (IAL) is not merely an endpoint event, but actually a phenomenon actively involved in the pathophysiology of various inflammatory disorders. The VEGF-C/VEGFR-3 and VEGF-A/VEGF-R2 signaling pathways are two of the best-studied pathways in IAL. Methods targeting these molecules, such as prolymphangiogenic or antilymphatic treatments, were found to be beneficial in various preclinical and/or clinical studies. This Review focuses on the most recent achievements in the fields of lymphatic biology relevant to inflammatory conditions. Additionally, preclinical and clinical therapies that modulate IAL are summarized.


Subject(s)
Lymphangiogenesis , Angiogenic Proteins/physiology , Animals , Diabetes Mellitus/immunology , Diabetes Mellitus/physiopathology , Graft Rejection/immunology , Graft Rejection/physiopathology , Humans , Inflammation/physiopathology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/physiopathology , Respiratory System/immunology , Respiratory System/physiopathology , Signal Transduction
19.
Br J Dermatol ; 171(2): 220-33, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24641095

ABSTRACT

Malignant melanoma represents < 10% of all skin cancers but is responsible for the majority of skin-cancer-related deaths. Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. Fortunately, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. Angiogenesis has been considered an important target for cancer treatment. Initial efforts have focused primarily on targeting endothelial and tumour-related vascular endothelial growth factor signalling. Here, we review different mechanisms of tumour vascularization described in melanoma and discuss the potential clinical implications.


Subject(s)
Melanoma/blood supply , Skin Neoplasms/blood supply , Angiogenesis Inhibitors/therapeutic use , Angiogenic Proteins/physiology , Clinical Trials as Topic , Humans , Lymphangiogenesis/physiology , Melanoma/drug therapy , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/physiopathology , Oncogenes/physiology , Skin Neoplasms/drug therapy , Melanoma, Cutaneous Malignant
20.
J Clin Invest ; 123(8): 3190-200, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23908119

ABSTRACT

Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/therapeutic use , Angiogenic Proteins/physiology , Animals , Cell Proliferation , Chemotaxis , Endothelial Cells/physiology , Humans , Molecular Targeted Therapy , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Vascular Endothelial Growth Factor Receptor-3/physiology
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