Coronary vessel development is dependent on the type III transforming growth factor β receptor
Coronary vessel development is dependent on the type III transforming growth factor β receptor
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DOI：
10.1161/circresaha.107.152082
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发表时间：
2007-10-12
影响因子：
20.1
通讯作者：
Barnett, Joey V.
中科院分区：
文献类型：
--
作者：
Compton, Leigh A.;Potash, Dru A.;Barnett, Joey V.
转化生长因子(TGF) β受体III （TGF β R3）或β -聚糖与所有3种TGF β配体和抑制素具有高亲和力，但缺乏I型和II型受体（TGF β R1, TGF β R2）中发现的丝氨酸/苏氨酸激酶结构域。TGF β R3促进TGF β R1/TGF β R2的信号传导，但也被认为在TGF β信号传导中发挥独特而非冗余的作用。Tgfbr3的靶向缺失揭示了冠状血管发育过程中对Tgfbr3的需求。无药小鼠冠状动脉血管生成明显受损，可见少量血管，心外膜可见大量持续的血岛。tgfbr3缺失小鼠在胚胎14.5天死亡，这是胚胎存活所需的功能冠状血管的时间。然而，在胚胎第14天，小鼠新生冠状血管附着在主动脉上，形成2个冠状动脉口，并开始平滑肌再生。早期发育阶段的分析显示心外膜有缺陷。在胚胎第13.5天，这些缺陷包括不规则和高细胞心外膜，心外膜下有丰富的间质和薄致密带心肌。tgfbr3缺失小鼠在冠状动脉发育方面也表现出其他缺陷，包括沿房室沟的血管畸形和扩张以及心外膜下出血。在无菌小鼠中，贯穿卵黄囊和胚胎的血管形成和招募平滑肌的模式与杂合子或野生型幼崽没有什么区别。这些数据表明，冠状血管发育过程中需要Tgfbr3，这对胚胎生存能力至关重要。
Transforming growth factor (TGF) beta receptor III (TGF beta R3), or beta-glycan, binds all 3 TGF beta ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGF beta R1, TGF beta R2). TGF beta R3 facilitates signaling via TGF beta R1/TGF beta R2 but also has been suggested to play a unique and nonredundant role in TGF beta signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability.