Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia.
Int J Mol Sci. 2021 Jul 20;22(14):7760. doi: 10.3390/ijms22147760.
The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.
淋巴管在人类众多疾病中的重要性正迅速得到认可；淋巴管功能障碍是包括先天性淋巴管异常、原发性淋巴水肿和肥胖症等疾病的特征，而改善淋巴管功能可提高癌症和神经疾病免疫疗法的疗效，并促进心肌梗死后的心脏修复。因此，了解淋巴管的生长和功能是如何精确调节的，对于为广泛的人类疾病开发新的治疗方法具有重要意义。淋巴管的发育是在胚胎发生过程中，主要血管建立和血流开始后启动的。淋巴管内皮祖细胞来源于静脉和非静脉来源的组合，以在脊椎动物胚胎中产生最初的淋巴管结构，然后进一步分支和重塑，以精细构建广泛的淋巴管网络。血管内皮生长因子（VEGF）家族成员和血管内皮生长因子受体（VEGFR）酪氨酸激酶介导的信号对于血液和淋巴管网络的发育至关重要，但在每个血管隔室中，不同程度地利用了不同的成分。尽管人们对血管内皮生长因子（VEGF）/血管内皮生长因子受体（VEGFR）2 信号在血管中的调节有了很多了解，但对于血管内皮生长因子（VEGF）C/血管内皮生长因子（VEGF）D/血管内皮生长因子受体（VEGFR）3 信号在淋巴管发育过程中是如何调节的机制了解较少。这篇综述将重点介绍我们对调节 VEGFA、VEGFC 和 VEGFD 介导的通过 VEGFR 信号的细胞和分子机制的最新理解，这些机制对于在发育和疾病过程中驱动淋巴管的构建很重要。
