Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review).
Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review).
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DOI：
10.3892/ijmm.2013.1444
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发表时间：
2013-10
影响因子：
5.4
通讯作者：
Katoh M
中科院分区：
文献类型：
--
作者：
Katoh M
血管生成是由原有血管形成新血管的过程，包括血管失稳、新生血管萌发、管腔形成和血管稳定的一系列步骤。血管内皮生长因子、成纤维细胞生长因子、血管生成素、Notch、转化生长因子-β、Hedgehog和WNT信号通路通过直接或间接调控内皮细胞的静止、迁移和增殖来调控血管生成。小分子化合物和阻断血管内皮生长因子信号转导的人/人源化单抗已被开发为癌症和新生血管老年性黄斑变性(AMD)的抗血管生成治疗药物。携带血管内皮生长因子、FGF2或FGF4的基因或蛋白治疗，以及使用内皮祖细胞、间充质干细胞(MSCs)或诱导多能干细胞(IPSCs)的细胞治疗，已被开发为缺血性心脏病和外周血管疾病的促血管生成治疗药物。对于癌症和新生血管的AMD，抗血管生成治疗比心血管疾病的促血管生成治疗更成功，因为与血管重建相比，阻断血管内皮生长因子信号在技术上是可行的。分别使用基于阵列的技术和个人基因组测序来检测常见和罕见的遗传变异。药物和剂量应根据个人的基因型别的血管内皮生长因子和其他参与血管生成。由于表观遗传改变会导致人类疾病，基于聚合物的水凝胶膜可能被用于输送针对表观遗传过程和血管生成的药物作为心血管疾病的治疗方式。外切体和微囊中的循环microRNAs(MiRNAs)被用作诊断和预后的功能生物标志物，而聚合物纳米粒中的合成miRNAs则适用于治疗。为了优化靶向治疗，需要对调节信号级联的时空相互作用以及个人基因分型和miRNA图谱的进展有更深刻的理解。
Angiogenesis is a process of neovascular formation from pre-existing blood vessels, which consists of sequential steps for vascular destabilization, angiogenic sprouting, lumen formation and vascular stabilization. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, Notch, transforming growth factor-β (TGF-β), Hedgehog and WNT signaling cascades orchestrate angiogenesis through the direct or indirect regulation of quiescence, migration and the proliferation of endothelial cells. Small-molecule compounds and human/humanized monoclonal antibodies interrupting VEGF signaling have been developed as anti-angiogenic therapeutics for cancer and neovascular age-related macular degeneration (AMD). Gene or protein therapy delivering VEGF, FGF2 or FGF4, as well as cell therapy using endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been developed as pro-angiogenic therapeutics for ischemic heart disease and peripheral vascular disease. Anti-angiogenic therapy for cancer and neovascular AMD is more successful than pro-angiogenic therapy for cardiovascular diseases, as VEGF-signal interruption is technically feasible compared with vascular re-construction. Common and rare genetic variants are detected using array-based technology and personal genome sequencing, respectively. Drug and dosage should be determined based on personal genotypes of VEGF and other genes involved in angiogenesis. As epigenetic alterations give rise to human diseases, polymer-based hydrogel film may be utilized for the delivery of drugs targeting epigenetic processes and angiogenesis as treatment modalities for cardiovascular diseases. Circulating microRNAs (miRNAs) in exosomes and microvesicles are applied as functional biomarkers for diagnostics and prognostics, while synthetic miRNAs in polymer-based nanoparticles are applicable for therapeutics. A more profound understanding of the spatio-temporal interactions of regulatory signaling cascades and advances in personal genotyping and miRNA profiling are required for the optimization of targeted therapy.
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