Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave, 76-361, Cambridge, MA, 02139, USA.
University of Suffolk, James Hehir Building, University Avenue, Ipswich, Suffolk, IP3 0FS, UK.
Angiogenesis. 2017 Nov;20(4):519-531. doi: 10.1007/s10456-017-9563-8. Epub 2017 Jun 30.
Fibronectin containing alternatively spliced EIIIA and EIIIB domains is largely absent from mature quiescent vessels in adults, but is highly expressed around blood vessels during developmental and pathological angiogenesis. The precise functions of fibronectin and its splice variants during developmental angiogenesis however remain unclear due to the presence of cardiac, somitic, mesodermal and neural defects in existing global fibronectin KO mouse models. Using a rare family of surviving EIIIA EIIIB double KO mice, as well as inducible endothelial-specific fibronectin-deficient mutant mice, we show that vascular development in the neonatal retina is regulated in an autocrine manner by endothelium-derived fibronectin, and requires both EIIIA and EIIIB domains and the RGD-binding α5 and αv integrins for its function. Exogenous sources of fibronectin do not fully substitute for the autocrine function of endothelial fibronectin, demonstrating that fibronectins from different sources contribute differentially to specific aspects of angiogenesis.
含有交替剪接 EIIIA 和 EIIIB 结构域的纤连蛋白在成人成熟静止血管中基本不存在，但在发育和病理性血管生成过程中高度表达于血管周围。由于现有的全局纤连蛋白 KO 小鼠模型存在心脏、体节、中胚层和神经缺陷，因此纤连蛋白及其剪接变体在发育性血管生成中的精确功能仍不清楚。利用罕见的 EIIIA EIIIB 双重 KO 小鼠家族，以及诱导型内皮特异性纤连蛋白缺陷突变小鼠，我们表明，新生儿视网膜中的血管发育受到内皮细胞衍生的纤连蛋白的自分泌调节，并且需要 EIIIA 和 EIIIB 结构域以及 RGD 结合的 α5 和 αv 整合素来发挥其功能。纤连蛋白的外源性来源不能完全替代内皮纤连蛋白的自分泌功能，表明不同来源的纤连蛋白对血管生成的特定方面有不同的贡献。
