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Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.

Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1). EC-specific Phd2 disruption suppressed retinal angiogenesis, despite HIFα accumulation and VEGFA upregulation. Suppressed ret

A novel flavonoid derivative for treating colorectal cancer by suppressing tumor angiogenesis through VEGFR2 inhibition.

INTRODUCTION: Inhibiting tumor angiogenesis is a recognized anticancer strategy. VEGFR2 is a key driver of pathological angiogenesis via VEGF signaling. Natural chalcones can target VEGFR2 but are limited by weak activity and low yield. OBJECTIVE: To design and synthesize novel chalcones as VEGFR2 inhibitors to suppress tumor angiogenesis, thereby offering a new anti-angiogenic strategy for colorectal cancer (CRC). METHODS: A series of novel chalcones was synthesized, and compound 27j, bearing a bis-Michael acceptor moiety, was selected. Its binding affinity to VEGFR2 was assessed by surface

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.

BACKGROUND: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (loc … tment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.

Antiglioma effects of a new, low molecular mass, inhibitor of fibroblast growth factor.

Despite the deployment of multimodal therapies involving neurosurgical resection, radio- and polychemotherapy, the prognosis for glioblastoma patients remains poor. These tumors are pathologically characterized by their associated angiogenesis and diffuse brain invasion, processes that are probably closely linked to the unfavorable prognosis of this disease. Accordingly, pharmacological inhibition of glioblastoma invasion and approaches that impede angiogenesis are considered to be promising therapeutic strategies to combat these tumors. Nevertheless, the anti-angiogenic therapies for glioblas

Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2.

Cyclosporin A (CsA) is an immunosuppressive drug that inhibits the activity of transcription factors of the nuclear factor of activated T cells (NFAT) family, interfering with the induction of cytokines and other inducible genes required for the immune response. Here we show that CsA inhibits migration of primary endothelial cells and angiogenesis induced by vascular endothelial growth factor (VEGF); this effect appears to be mediated through the inhibition of cyclooxygenase (Cox)-2, the transcription of which is activated by VEGF in primary endothelial cells. Consistent with this, we show tha

The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration.

Acellular nerve allografts (ANAs) are increasingly used to repair nerve gaps following injuries. However, these nerve scaffolds have yet to surpass the regenerative capabilities of cellular nerve autografts; improved understanding of their regenerative mechanisms could improve design. Due to their acellular nature, both angiogenesis and diverse cell recruitment is necessary to repopulate these scaffolds to promote functional regeneration. We determined the contribution of angiogenesis to initial cellular repopulation of ANAs used to repair nerve gaps, as well as the signaling that drives a sig

Role of angiogenic factors in acute experimental Strongyloides venezuelensis infection.

This study aims to investigate the role of angiogenic factors in the pathogenesis of experimental strongyloidiasis. Two complementary approaches were used: Firstly, CD1 mice were treated with endostatin, an angiogenesis inhibitor, and infected with Strongyloides venezuelensis. Also, the mechanisms involved in this process were studied. Parasitological examination revealed a significant decrease in egg per gram of faeces, number of collected larvae from lung tissue and number of collected adult females in mice treated with endostatin. Direct mechanisms with diminution of angiogenesis factors an

Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.

Liver injury causes vascular disorganization and local tissue hypoxia starting early in disease course. In this context, hypoxia acts not only as an aggravating factor of cell damage and inflammation, but also as an inhibitor of liver regeneration, a major stimulus of angiogenesis and fibrogenesis, and a promoter of liver carcinogenesis. Many of the effects of hypoxia are mediated by hypoxia-inducible factor-1alpha (HIF-1alpha), an oxygen-sensitive transcription factor. Compared to cells in the periportal area, intralobular hepatic stellate cells (HSCs) are more responsive to hypoxia and like

PGC-1α-mediated angiogenesis prevents pulmonary hypertension in mice.

Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhi

Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors.

Stem cells are characterized by the capacity for both self-renewal and generation of all other cell types (pluripotency) or differentiated cells within a particular lineage (multipotency). Stem cells are often localized to hypoxic niches within tissues and hypoxia inducible factors (HIFs) play key roles in the maintenance of pluripotent and multipotent stem cells, as well as cancer stem cells, which are also known as tumor-initiating cells. HIF inhibitors target cancer stem cells and improve the responses to angiogenesis inhibitors and cytotoxic chemotherapy in mouse models of breast cancer.

Hypoxia-induced tumor exosomes promote angiogenesis through miR-1825/TSC2/mTOR axis in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is characterized by enhanced angiogenesis resulting in poor prognosis despite improvements in diagnostic/therapeutic techniques. Here, we aimed at investigating potential roles of miR-1825 enclosed in OSCC-derived exosomes on angiogenesis under hypoxic conditions. METHODS: Effects of miR-1825 mimic/inhibitor as well as hypoxia-induced tumor derived exosomes on human umbilical vein endothelial cells (HUVECs) were evaluated using cell viability, migration/invasion, tube formation, and spheroid-based 3D angiogenesis assays. RESULTS: Hypoxic condit

TRAP1 and its therapeutic potential.

The mitochondrial Hsp90 isoform, Tumor Necrosis Factor Receptor Associated Protein 1 (TRAP1), is central to the pathogenesis of disease states that include cancer, ischemic retinopathy, and diabetic kidney disease among others. TRAP1 contributes to these diseases through the regulation of mitochondrial metabolism, apoptosis, oxidative stress, cell signaling and angiogenesis through interactions with client proteins. Numerous TRAP1-selective inhibitors have been developed to limit the toxicities associated with Hsp90 pan-inhibition, while leveraging the therapeutic benefits of TRAP1 inhibition.

[Oral toxicity of targeted anticancer therapies].

While toxicity of targeted anticancer therapies on the oral mucosa seems relatively frequent in clinical practice, it has not been properly characterized to date, apart from aphthous-like lesions due to mTOR inhibitors. Herein, we report the main oral lesions associated with these new therapies, with a description of the most frequent but also the most characteristic clinical manifestations of these drugs, such as anti-EGFR-induced mucositis, BRAF-inhibitor-associated hyperkeratosis, benign migratory glossitis and osteonecrosis of the jaw observed with angiogenesis inhibitors, as well as lesio…

Cardiotoxicity of cancer chemotherapy: identification, prevention and treatment.

Cardiotoxicity is an important complication of several cancer therapeutic agents. Several well established and newer anticancer therapies such as anthracyclines, trastuzumab and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors (TKIs), angiogenesis inhibitors, and checkpoint inhibitors are associated with significant cardiotoxicity. Cardiovascular imaging employing radionuclide imaging, echocardiography and magnetic resonance imaging are helpful in early detection and prevention of overt heart failure secondary to cardiotoxicity of cancer therapy. An …

Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs.

The main group of enzymes responsible for the collagen and other protein degradation in extracellular matrix (ECM) are matrix metalloproteinases (MMPs). Collagen is the main structural component of connective tissue and its degradation is a very important process in the development, morphogenesis, tissue remodeling, and repair. Typical structure of MMPs consists of several distinct domains. MMP family can be divided into six groups: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other non-classified MMPs. MMPs and their inhibitors have multiple biological functio

The Mediterranean Diet, a Rich Source of Angiopreventive Compounds in Cancer.

Diet-based chemoprevention of cancer has emerged as an interesting approach to evade the disease or even target its early phases, reducing its incidence or slowing down tumor progression. In its basis in the essential role of angiogenesis for tumor growth and metastasis, angioprevention proposes the use of inhibitors of angiogenesis in cancer prevention. The anti-angiogenic potential exhibited by many natural compounds contained in many Mediterranean diet constituents makes this dietary pattern especially interesting as a source of chemopreventive agents, defined within the angioprevention str

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… With a similar chemical structure to that of delphinidin, its role as an angiogenesis inhibitor has been studied in different cancer types, being reported to inhibit the PI3-K/Akt pathway, both in tumor and endothelial cells [ 125 ]. … Angiogenesis inhibitors as therapeutic agents in cancer: Challenges and future directions. Eur. J. Pharmacol. 2016;793:76–81. doi: 10.1016/j.ejphar.2016.10.039. 15. Ramjiawan R.R., Griffioen A.W., Duda D.G. …

PPARalpha deficiency in inflammatory cells suppresses tumor growth.

Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)alpha is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARalpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARalpha expressing granulocytes are necessary for tumor growth. Neutralization of thrombospo

Inhibition of angiogenesis impairs bone healing in an in vivo murine rapid resynostosis model.

Biologics can improve bone formation, but may diffuse away from sites of therapeutic need. We developed a click-chemistry hydrogel that rapidly polymerizes in situ to control delivery of biologics during post-suturectomy resynostosis in 21-day-old male mice. Here, we used this model to determine the role of angiogenesis in post-suturectomy resynostosis and examine whether controlled release of angiogenesis inhibitors could delay bone regeneration. Hydrogels [DB-co-PEG/poly (TEGDMA)-co-(N3-TEGDMA)] were produced containing anti-angiogenic compounds [anti-VEGFA-antibody or hypoxia inducible fact…

A Promising Paradigm Shift in Cancer Treatment with FGFR Inhibitors.

FGFR have been demonstrated to perform a crucial role in biological processes but their overexpression has been perceived as the operator component in the occurrence and progression of different types of carcinoma. Out of all the interest around cancer, FGFR inhibitors have assembled pace over the past few years. Therefore, FGFR inhibitors are one of the main fundamental tools to reverse drug resistance, tumor growth, and angiogenesis. Currently, many FGFR inhibitors are under the development stage or have been developed. Due to great demand and hotspots, different pharmacophores were approach

Therapeutic effects of histone deacetylase inhibitors on heart disease.

A wide range of histone deacetylase (HDAC) inhibitors have been studied for their therapeutic potential because the excessive activity and expression of HDACs have been implicated in the pathogenesis of cardiac diseases. An increasing number of preclinical studies have demonstrated the cardioprotective effects of numerous HDAC inhibitors, suggesting a wide variety of mechanisms by which the inhibitors protect against cardiac stress, such as the suppression of cardiac fibrosis and fetal gene expression, enhancement of angiogenesis and mitochondrial biogenesis, prevention of electrical remodelin