Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.).
Multidisciplinary PhD Program in Biomedical Sciences: Molecular Biology, Genetics, and Cancer Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., S.A.).
Circ Res. 2021 Feb 5;128(3):e27-e44. doi: 10.1161/CIRCRESAHA.120.318200. Epub 2020 Nov 30.
Defects in the morphogenesis of the fourth pharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease.
Cell-ECM (extracellular matrix) interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin α5β1 and Fn1 (fibronectin) expressed in the lineages regulate PAA formation. The objective of the current studies was to investigate cellular mechanisms by which integrin α5β1 and Fn1 regulate aortic arch artery morphogenesis.
Using temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and contribute to pharyngeal arch endothelium between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches form a plexus of small blood vessels, which remodels into the PAAs by 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on the pharyngeal ECM microenvironment, extrinsic to the endothelium. Conditional ablation of integrin α5β1 or Fn1 in the lineages showed that signaling by the ECM regulates aortic arch artery morphogenesis at multiple steps: (1) accumulation of SHF-derived ECs in the pharyngeal arches, (2) remodeling of the EC plexus in the fourth arches into the PAAs, and (3) differentiation of neural crest-derived cells adjacent to the PAA endothelium into vascular smooth muscle cells.
PAA formation is a multistep process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the aortic arch artery and its major branches. Cell-ECM interactions regulated by integrin α5β1 and Fn1 play essential roles at each of these developmental stages.
第四咽弓动脉（PAAs）形态发生缺陷会导致致命的出生缺陷。了解调节 PAA 形成的基因和机制将为先天性心脏病的病因和治疗提供重要的见解。
细胞-细胞外基质（ECM）相互作用在 PAA 及其衍生物（主动脉弓动脉及其主要分支）的形态发生中起着至关重要的作用；然而，其具体功能尚未得到很好的理解。之前，我们证明了在谱系中表达的整合素α5β1 和 Fn1（纤连蛋白）调节 PAA 的形成。本研究的目的是研究整合素α5β1 和 Fn1 调节主动脉弓动脉形态发生的细胞机制。
使用时间谱系追踪、全胚胎共聚焦成像和第二心脏场（SHF）和内皮细胞（EC）动力学的定量分析，我们表明大多数 PAA EC 祖细胞在 SHF 中于 E7.5 出现，并在 E7.5 和 E9.5 之间贡献咽弓内皮。因此，咽弓中的 SHF 衍生 EC 形成小血管丛，该血管丛在 35 体节处重塑为 PAA。血管丛的重塑是由依赖于咽 ECM 微环境的信号协调的，该信号位于内皮之外。在 谱系中条件性敲除整合素α5β1 或 Fn1 表明，ECM 信号在多个步骤调节主动脉弓动脉形态发生：（1）SHF 衍生的 EC 在咽弓中的积累，（2）第四咽弓中 EC 丛的重塑为 PAA，以及（3）与 PAA 内皮相邻的神经嵴衍生细胞分化为血管平滑肌细胞。
PAA 的形成是一个多步骤的过程，需要 SHF 衍生的 EC 动态地向咽弓贡献，内皮丛重塑为 PAA，以及 PAA 重塑为主动脉弓动脉及其主要分支。整合素α5β1 和 Fn1 调节的细胞-ECM 相互作用在这些发育阶段都起着至关重要的作用。
