{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVascular endothelial growth factor A (VEGFA) serves as a master regulator of angiogenesis by stimulating endothelial cell proliferation, migration, and vascular permeability. Genetic studies have revealed that mutations in non‐coding regions of the VEGFA gene contribute to inter‐individual variability in circulating levels ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. In addition, VEGFA acts as a chemoattractant and mitogen for osteoblasts, thereby participating in bone formation and remodeling ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]. Environmental cues such as copper exposure can induce VEGFA expression in keratinocytes, which accelerates cutaneous wound repair ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]. Redox regulators like thioredoxin‑1 further enhance VEGFA production by stabilizing hypoxia‐inducible factors ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "], and synergistic interactions with bone morphogenetic proteins reinforce its role in endochondral ossification ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]. Genetic polymorphisms in the VEGFA promoter that augment transcriptional activity have also been documented ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "], while structural control via G‑quadruplex formation in the promoter region offers another layer of transcriptional regulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn malignant contexts, oncogenic pathways play a pivotal role in driving VEGFA up‑regulation. Activated STAT3 directly binds the VEGFA promoter in diverse tumor cells, thereby fueling angiogenesis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. In colon carcinoma, insulin‑like growth factor‑1 induces VEGFA expression in a hypoxia‑inducible factor‑1α–dependent manner ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "], and redox‐dependent stabilization of HIF‑1α further amplifies its levels ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]. Moreover, clinical evidence links VEGFA gene polymorphisms to microvascular complications such as diabetic retinopathy ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "] and therapeutic applications of VEGFA gene transfer have been explored in coronary heart disease ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]. In cholangiocarcinoma, co‑expression of biomarkers including VEGFA correlates with advanced tumor progression ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nVEGFA further functions in neoplastic advancement through both autocrine and paracrine mechanisms. In breast carcinoma cells, VEGFA acts in an autocrine fashion to regulate chemokine receptor expression and promote invasive migration ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]. In pancreatic cancer, constitutive STAT3 activation directly enhances VEGFA transcription, contributing to an aggressive angiogenic phenotype ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. Elevated basal expression due to promoter polymorphisms has been linked to altered VEGFA levels in cancerous tissues ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "]. Furthermore, interleukin‑6 signaling in cervical cancer drives VEGFA‑mediated angiogenesis via a STAT3 pathway, thereby stimulating tumor growth ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic roles, VEGFA is fundamental to neural function and tissue repair. In neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), reduced VEGFA expression is associated with motor neuron degeneration, while experimental supplementation protects vulnerable neurons ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "]. Topically applied recombinant VEGFA accelerates wound closure in diabetic models by promoting granulation tissue formation and mobilizing endothelial precursors ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "]. In hypoxic tumor regions, Src kinase and HIF‑1α pathways cooperate to further induce VEGFA expression ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "]. The fine‑tuning of its transcription is exemplified by regulatory G‑quadruplex structures within its promoter, offering potential targets for therapeutic modulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNon‑coding RNAs contribute significantly to the dynamic regulation of VEGFA in cancer. Circular RNA MYLK functions as a competing endogenous RNA by sponging miR‑29a, thereby relieving suppression of VEGFA and promoting epithelial–mesenchymal transition in bladder carcinoma ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "]. Similarly, a complex network of microRNAs modulates VEGFA expression in nasopharyngeal carcinoma, illustrating a differential and coordinated regulatory mechanism ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "]. In the retina, VEGFA exerts direct neuroprotective effects by reducing apoptosis following ischemic injury ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "]. Moreover, dysregulated metabolic pathways—such as those involving HIF‑1α in conjunction with aberrant c‑Myc activity—further elevate VEGFA expression and reprogram cancer cell metabolism ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "]. Elevated reactive oxygen species in ovarian cancer also stimulate VEGFA production through HIF‑1 activation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "], and in cholangiocarcinoma, overexpression of VEGFA correlates with tumor aggressiveness ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "]. Metabolic regulators such as visfatin additionally modulate VEGFA levels and matrix metalloproteinase activity, reinforcing the angiogenic switch within tumors ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenomic alterations further underscore the oncogenic impact of VEGFA. Focal copy gains of the VEGFA locus in hepatocellular carcinoma exemplify how genomic amplification can drive non‑cell‑autonomous oncogene activation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "]. In breast cancer, specific VEGFA genotypes have been associated with differential responses to anti‑angiogenic therapy, suggesting a role as a predictive biomarker ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "]. Paradoxically, VEGFA can also destabilize nascent vessels by interfering with platelet‑derived growth factor receptor signaling, thus disrupting pericyte coverage and vessel maturation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "]. In ALS models, diminished VEGFA exacerbates motor neuron loss while its supplementation delays paralysis, confirming its neuroprotective capacity ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "]. Additionally, tumor‑derived microvesicles containing activated epidermal growth factor receptor (EGFR) can initiate VEGFA expression in endothelial cells, establishing an autocrine loop that reinforces angiogenesis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": "]. In the central nervous system, VEGFA leads to blood–brain barrier breakdown by downregulating tight junction proteins ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "], and its pharmacological inhibition in metastatic colorectal cancer has been associated with reduced levels of regulatory T cells ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn regenerative medicine and metabolic disorders the modulation of VEGFA is equally critical. Hypoxic preconditioning of adipose‑derived stem cells enhances VEGFA secretion and improves wound healing outcomes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": "], whereas diabetic conditions impair hypoxia‑induced VEGFA upregulation due to defective HIF‑1α/p300 interactions, contributing to poor neovascularization ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "]. Furthermore, genome‑wide association analyses have identified VEGFA as one of several loci influencing renal function and susceptibility to chronic kidney disease ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": "], and variation within the VEGFA locus has also been linked to differences in body fat distribution independent of total adiposity ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent insights into VEGFA’s roles in tumor progression have added further layers to its complexity. In glioblastoma models, inhibition of VEGFA signaling can paradoxically elicit a pro‑invasive phenotype by activating MET and triggering an epithelial–mesenchymal transition ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "]. Moreover, VEGFA directly stimulates the proliferation of regulatory T cells via VEGFR2, thereby contributing to an immunosuppressive tumor microenvironment ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "39"}]}, {"type": "t", "text": "]. In broad clinical reviews, VEGFA is recognized as essential not only for tumor angiogenesis but also for sustaining cancer stem cell functions and tumor initiation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "40"}]}, {"type": "t", "text": "]. High‑resolution imaging studies have further documented transient VEGFA‑mediated vascular permeability events at tumor microenvironmental sites that facilitate tumor cell intravasation and metastasis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "42"}]}, {"type": "t", "text": "]. Taken together, these findings have paved the way for combination strategies that target both VEGFA and angiopoietin‑2 to normalize tumor vessels, enhance immune effector cell infiltration, and ultimately improve immunotherapy outcomes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "43"}]}, {"type": "t", "text": "].\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "W Renner, S Kotschan, C Hoffmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Vasc Res (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000054076"}], "href": "https://doi.org/10.1159/000054076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11146397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11146397"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "N Ferrara, H P Gerber "}, {"type": "b", "children": [{"type": "t", "text": "The role of vascular endothelial growth factor in angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Haematol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000046610"}], "href": "https://doi.org/10.1159/000046610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11815711"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11815711"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "U Mayr-Wohlfart, J Waltenberger, H Hausser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bone (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s8756-3282(01)00690-1"}], "href": "https://doi.org/10.1016/s8756-3282(01"}, {"type": "t", "text": "00690-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11882460"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11882460"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chandan K Sen, Savita Khanna, Mika Venojarvi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Copper-induced vascular endothelial growth factor expression and wound healing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.01015.2001"}], "href": "https://doi.org/10.1152/ajpheart.01015.2001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11959648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11959648"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sarah J Welsh, William T Bellamy, Margaret M Briehl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12208766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12208766"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hairong Peng, Vonda Wright, Arvydas Usas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI15153"}], "href": "https://doi.org/10.1172/JCI15153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12235106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12235106"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Daoyan Wei, Xiangdong Le, Leizhen Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206122"}], "href": "https://doi.org/10.1038/sj.onc.1206122"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12545153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12545153"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Daekyu Sun, Kexiao Guo, Jadrian J Rusche, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gki917"}], "href": "https://doi.org/10.1093/nar/gki917"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16239639"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16239639"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Guilian Niu, Kenneth L Wright, Mei Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1205260"}], "href": "https://doi.org/10.1038/sj.onc.1205260"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11960372"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11960372"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ryo Fukuda, Kiichi Hirota, Fan Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M203781200"}], "href": "https://doi.org/10.1074/jbc.M203781200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12149254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12149254"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Takuya Awata, Kiyoaki Inoue, Susumu Kurihara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/diabetes.51.5.1635"}], "href": "https://doi.org/10.2337/diabetes.51.5.1635"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11978667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11978667"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Sarah L McCarron, Stephen Edwards, Philip R Evans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Influence of cytokine gene polymorphisms on the development of prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12067976"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12067976"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Gakuji Hashimoto, Isao Inoki, Yutaka Fujii, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M201674200"}], "href": "https://doi.org/10.1074/jbc.M201674200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12114504"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12114504"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Robin E Bachelder, Melissa A Wendt, Arthur M Mercurio "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12499259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12499259"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Adam Stevens, Joanne Soden, Paul E Brenchley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12591731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12591731"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Lin-Hung Wei, Min-Liang Kuo, Chi-An Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206226"}], "href": "https://doi.org/10.1038/sj.onc.1206226"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12629515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12629515"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Diether Lambrechts, Erik Storkebaum, Masafumi Morimoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1211"}], "href": "https://doi.org/10.1038/ng1211"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12847526"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12847526"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Robert D Galiano, Oren M Tepper, Catherine R Pelo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)63754-6"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "63754-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15161630"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15161630"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Michael J Gray, Jing Zhang, Lee M Ellis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208513"}], "href": "https://doi.org/10.1038/sj.onc.1208513"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15735682"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15735682"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Jean-Philippe Coppé, Katalin Kauser, Judith Campisi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M603307200"}], "href": "https://doi.org/10.1074/jbc.M603307200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16880208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16880208"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Zhong Hua, Qing Lv, Wenbin Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0000116"}], "href": "https://doi.org/10.1371/journal.pone.0000116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17205120"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17205120"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Kazuaki Nishijima, Yin-Shan Ng, Lichun Zhong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2007.061237"}], "href": "https://doi.org/10.2353/ajpath.2007.061237"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17591953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17591953"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Jung-whan Kim, Ping Gao, Yen-Chun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00440-07"}], "href": "https://doi.org/10.1128/MCB.00440-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17785433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17785433"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Chang Xia, Qiao Meng, Ling-Zhi Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-0783"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-0783"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18006827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18006827"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "D Yoshikawa, H Ojima, M Iwasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6604129"}], "href": "https://doi.org/10.1038/sj.bjc.6604129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18087285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18087285"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Raghu Adya, Bee K Tan, Anu Punn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvm111"}], "href": "https://doi.org/10.1093/cvr/cvm111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18093986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18093986"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Derek Y Chiang, Augusto Villanueva, Yujin Hoshida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Focal gains of VEGFA and molecular classification of hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-08-0742"}], "href": "https://doi.org/10.1158/0008-5472.CAN-08-0742"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18701503"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18701503"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Bryan P Schneider, Molin Wang, Milan Radovich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2008.16.1612"}], "href": "https://doi.org/10.1200/JCO.2008.16.1612"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18824714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18824714"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Joshua I Greenberg, David J Shields, Samuel G Barillas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A role for VEGF as a negative regulator of pericyte function and vessel maturation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature07424"}], "href": "https://doi.org/10.1038/nature07424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18997771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18997771"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Philip Bao, Arber Kodra, Marjana Tomic-Canic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of vascular endothelial growth factor in wound healing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Surg Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jss.2008.04.023"}], "href": "https://doi.org/10.1016/j.jss.2008.04.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19027922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19027922"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Daniel Martin, Rebeca Galisteo, J Silvio Gutkind "}, {"type": "b", "children": [{"type": "t", "text": "CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C800207200"}], "href": "https://doi.org/10.1074/jbc.C800207200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19112107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19112107"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Azeb Tadesse Argaw, Blake T Gurfein, Yueting Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0808698106"}], "href": "https://doi.org/10.1073/pnas.0808698106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19174516"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19174516"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Khalid Al-Nedawi, Brian Meehan, Robert S Kerbel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0804543106"}], "href": "https://doi.org/10.1073/pnas.0804543106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19234131"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19234131"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Eun Young Lee, Ying Xia, Won-Serk Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Wound Repair Regen (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1524-475X.2009.00499.x"}], "href": "https://doi.org/10.1111/j.1524-475X.2009.00499.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19614919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19614919"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Hariharan Thangarajah, Dachun Yao, Edward I Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0906670106"}], "href": "https://doi.org/10.1073/pnas.0906670106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19666581"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19666581"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Anna Köttgen, Cristian Pattaro, Carsten A Böger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New loci associated with kidney function and chronic kidney disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.568"}], "href": "https://doi.org/10.1038/ng.568"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20383146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20383146"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Iris M Heid, Anne U Jackson, Joshua C Randall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.685"}], "href": "https://doi.org/10.1038/ng.685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20935629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20935629"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Kan V Lu, Jeffrey P Chang, Christine A Parachoniak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2012.05.037"}], "href": "https://doi.org/10.1016/j.ccr.2012.05.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22789536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22789536"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Magali Terme, Simon Pernot, Elie Marcheteau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-2325"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-2325"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23108136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23108136"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Masabumi Shibuya "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biochem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jb/mvs136"}], "href": "https://doi.org/10.1093/jb/mvs136"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23172303"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23172303"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Hira Lal Goel, Arthur M Mercurio "}, {"type": "b", "children": [{"type": "t", "text": "VEGF targets the tumour cell."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nrc3627"}], "href": "https://doi.org/10.1038/nrc3627"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24263190"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24263190"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Allison S Harney, Esther N Arwert, David Entenberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-15-0012"}], "href": "https://doi.org/10.1158/2159-8290.CD-15-0012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26269515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26269515"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Dai Fukumura, Jonas Kloepper, Zohreh Amoozgar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Clin Oncol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nrclinonc.2018.29"}], "href": "https://doi.org/10.1038/nrclinonc.2018.29"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29508855"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29508855"}]}]}]}