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The Keio Journal of Medicine Mar 2022The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular... (Review)
Review
The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.
Topics: Eye; Humans; Infant, Newborn; Macular Degeneration; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 33840673
DOI: 10.2302/kjm.2021-0004-IR -
Medicina (Kaunas, Lithuania) Jul 2022Angiogenesis is the process of developing new blood vessels from pre-existing ones. This review summarizes the main features of physiological and pathological... (Review)
Review
Angiogenesis is the process of developing new blood vessels from pre-existing ones. This review summarizes the main features of physiological and pathological angiogenesis and those of angiogenesis activation and inhibition. In healthy adults, angiogenesis is absent apart from its involvement in female reproductive functions and tissue regeneration. Angiogenesis is a complex process regulated by the action of specific activators and inhibitors. In certain diseases, modulating the angiogenic balance can be a therapeutic route, either by inhibiting angiogenesis (for example in the case of tumor angiogenesis), or by trying to activate the process of new blood vessels formation, which is the goal in case of cardiac or peripheral ischemia.
Topics: Angiogenesis Inhibitors; Cardiovascular Diseases; Female; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 35888622
DOI: 10.3390/medicina58070903 -
International Journal of Molecular... May 2021Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and... (Review)
Review
Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.
Topics: Animals; Animals, Newborn; Chromogranins; Humans; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxygen; Retina; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A
PubMed: 34062733
DOI: 10.3390/ijms22094809 -
Journal of Immunology Research 2022Lactic acid is a "metabolic waste" product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has... (Review)
Review
Lactic acid is a "metabolic waste" product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells' effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.
Topics: Glycolysis; Humans; Lactic Acid; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 35733921
DOI: 10.1155/2022/3119375 -
International Journal of Molecular... Mar 2021Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and... (Review)
Review
Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors.
Topics: Apoptosis; Drug Resistance, Neoplasm; Humans; Melanoma; MicroRNAs; Neoplasm Invasiveness; Neovascularization, Pathologic; RNA, Neoplasm; bcl-X Protein
PubMed: 33803452
DOI: 10.3390/ijms22052777 -
Journal of Translational Medicine Sep 2023Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development...
BACKGROUND
Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization.
METHODS
Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1.
RESULTS
Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis.
CONCLUSION
In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.
Topics: Humans; Adaptor Proteins, Signal Transducing; Angiogenesis Inhibitors; Calcium-Binding Proteins; Endothelial Cells; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor A; Animals
PubMed: 37737201
DOI: 10.1186/s12967-023-04503-x -
JCI Insight Jun 2023Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In...
Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.
Topics: Humans; Interleukin-8; Neovascularization, Pathologic; Neoplasms; Paclitaxel; Oxygen; Tumor Microenvironment
PubMed: 37192004
DOI: 10.1172/jci.insight.161675 -
International Journal of Molecular... Aug 2020Angiogenesis is the process through which new blood vessels are formed from pre-existing ones. Exosomes are involved in angiogenesis in cancer progression by... (Review)
Review
Angiogenesis is the process through which new blood vessels are formed from pre-existing ones. Exosomes are involved in angiogenesis in cancer progression by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. Exosomes promote angiogenesis by suppressing expression of factor-inhibiting hypoxia-inducible factor 1 (HIF-1). Uptake of tumor-derived exosomes (TEX) by normal endothelial cells activates angiogenic signaling pathways in endothelial cells and stimulates new vessel formation. TEX-driven cross-talk of mesenchymal stem cells (MSCs) with immune cells blocks their anti-tumor activity. Effective inhibition of tumor angiogenesis may arrest tumor progression. Bevacizumab, a VEGF-specific antibody, was the first antiangiogenic agent to enter the clinic. The most important clinical problem associated with cancer therapy using VEGF- or VEFGR-targeting agents is drug resistance. Combined strategies based on angiogenesis inhibitors and immunotherapy effectively enhances therapies in various cancers, but effective treatment requires further research.
Topics: Angiogenesis Inhibitors; Animals; Endothelial Cells; Exosomes; Humans; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic
PubMed: 32823989
DOI: 10.3390/ijms21165840 -
International Journal of Molecular... Mar 2022Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis. Studies implicate vascular calcification as a...
Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis. Studies implicate vascular calcification as a contributor to PAD, but the mechanisms remain unclear. We aimed to determine the effect of calcification on ischaemia-driven angiogenesis. Human coronary artery endothelial cells (ECs) were treated with calcification medium (CM: CaCl 2.7 mM, NaPO 2.0 mM) for 24 h and exposed to normoxia (5% CO) or hypoxia (1.2% O; 5% CO balanced with N). In normoxia, CM significantly inhibited tubule formation and migration and upregulated calcification markers of ALP, BMP2, and Runx2. CM elevated levels of calcification-protective gene OPG, demonstrating a compensatory mechanism by ECs. CM failed to induce pro-angiogenic regulators VEGFA and HIF-1α in hypoxia and further suppressed the phosphorylation of endothelial nitric oxide synthase (eNOS) that is essential for vascular function. In vivo, osteoprotegerin-deficient mice (OPG), a calcification model, were subjected to hind-limb ischaemia (HLI) surgery. OPG mice displayed elevated serum alkaline phosphatase (ALP) activity compared to wild-type controls. OPG mice experienced striking reductions in blood-flow reperfusion in both 8-week-old and 6-month-old mice post-HLI. This coincided with significant impairment in tissue ischaemia and reduced limb function as assessed by clinical scoring (Tarlov). This study demonstrated for the first time that a pro-calcific environment is detrimental to ischaemia-driven angiogenesis. The degree of calcification in patients with PAD can often be a limiting factor with the use of standard therapies. These highly novel findings require further studies for full elucidation of the mechanisms involved and have implications for the development of therapies to suppress calcification in PAD.
Topics: Animals; Carbon Dioxide; Endothelial Cells; Humans; Hypoxia; Ischemia; Mice; Neovascularization, Pathologic; Peripheral Arterial Disease; Vascular Calcification
PubMed: 35328786
DOI: 10.3390/ijms23063363 -
FASEB Journal : Official Publication of... Nov 2020Angiogenesis involves the formation of new blood vessels from preexisting ones, and it is an essential step during cutaneous wound healing, which supports cells at the... (Review)
Review
Angiogenesis involves the formation of new blood vessels from preexisting ones, and it is an essential step during cutaneous wound healing, which supports cells at the wound site with nutrition and oxygen. Impaired angiogenesis in the wound tissues results in delayed wound closure and healing. Among the regulators of angiogenesis, the role of catecholamines (epinephrine, norepinephrine, and dopamine) is of interest due to their diverse roles in the process of wound healing. While both norepinephrine and epinephrine mostly inhibit the angiogenic process in cutaneous wounds, dopamine, the other member of the catecholamine family, has interesting and contradictory roles in the regulation of angiogenesis in the wound beds, depending on the type of dopamine receptor involved. The stimulation of dopamine D2 receptors negatively regulates the angiogenic process in normal dermal wounds and thereby delays healing, whereas the stimulation of dopamine D1 receptors promotes angiogenesis and expedites healing in diabetic wounds. Importantly, catecholamines also play important roles in other pathological conditions, and specific agonists and antagonists of catecholamines are available for the treatment of some disorders. Therefore, such drugs may be utilized for the management of angiogenesis to promote the healing of dermal wounds. This review provides a broad overview of the angiogenic process during cutaneous wound healing and the regulatory roles played by catecholamines during the process.
Topics: Animals; Catecholamines; Humans; Neovascularization, Pathologic; Skin Diseases; Wound Healing
PubMed: 32949437
DOI: 10.1096/fj.202001701R