Oscillatory contractile forces refine endothelial cell-cell interactions for continuous lumen formation governed by Heg1/Ccm1

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Jianmin Yin, Ludovico Maggi, Cora Wiesner, Markus Affolter, Heinz-Georg Belting
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Abstract

The formation and organization of complex blood vessel networks rely on various biophysical forces, yet the mechanisms governing endothelial cell-cell interactions under different mechanical inputs are not well understood. Using the dorsal longitudinal anastomotic vessel (DLAV) in zebrafish as a model, we studied the roles of multiple biophysical inputs and cerebral cavernous malformation (CCM)-related genes in angiogenesis. Our research identifies heg1 and krit1 (ccm1) as crucial for the formation of endothelial cell-cell interfaces during anastomosis. In mutants of these genes, cell-cell interfaces are entangled with fragmented apical domains. A Heg1 live reporter demonstrated that Heg1 is dynamically involved in the oscillatory constrictions along cell-cell junctions, whilst a Myosin live reporter indicated that heg1 and krit1 mutants lack actomyosin contractility along these junctions. In wild-type embryos, the oscillatory contractile forces at junctions refine endothelial cell-cell interactions by straightening junctions and eliminating excessive cell-cell interfaces. Conversely, in the absence of junctional contractility, the cell-cell interfaces become entangled and prone to collapse in both mutants, preventing the formation of a continuous luminal space. By restoring junctional contractility via optogenetic activation of RhoA, contorted junctions are straightened and disentangled. Additionally, haemodynamic forces complement actomyosin contractile forces in resolving entangled cell-cell interfaces in both wild-type and mutant embryos. Overall, our study reveals that oscillatory contractile forces governed by Heg1 and Krit1 are essential for maintaining proper endothelial cell-cell interfaces and thus for the formation of a continuous luminal space, which is essential to generate a functional vasculature.

Abstract Image

振荡收缩力完善了内皮细胞与细胞之间的相互作用,从而在 Heg1/Ccm1 的调控下形成连续的管腔。
复杂血管网络的形成和组织依赖于各种生物物理力,然而不同机械输入下的内皮细胞-细胞相互作用机制还不甚明了。我们以斑马鱼背侧纵向吻合血管(DLAV)为模型,研究了多种生物物理输入和脑海绵畸形(CCM)相关基因在血管生成中的作用。我们的研究发现,heg1 和 krit1(ccm1)对吻合过程中内皮细胞-细胞界面的形成至关重要。在这些基因的突变体中,细胞-细胞界面与破碎的顶端结构域纠缠在一起。Heg1 活体报告表明,Heg1 动态参与了沿细胞-细胞连接处的振荡收缩,而肌球蛋白活体报告表明,heg1 和 krit1 突变体缺乏沿这些连接处的肌动蛋白收缩能力。在野生型胚胎中,交界处的摆动收缩力通过拉直交界和消除过多的细胞-细胞界面来完善内皮细胞-细胞之间的相互作用。相反,在缺乏连接收缩力的情况下,两种突变体的细胞-细胞界面会纠缠在一起并容易塌陷,从而阻碍形成连续的管腔空间。通过光遗传激活 RhoA 来恢复交界收缩力,扭曲的交界就会被拉直和解开。此外,在解决野生型和突变型胚胎中缠结的细胞-细胞界面时,血液动力学力对肌动蛋白收缩力起到了补充作用。总之,我们的研究揭示了由 Heg1 和 Krit1 控制的振荡收缩力对于维持适当的内皮细胞-细胞界面,从而形成连续的管腔空间至关重要,而这对于生成功能性血管是必不可少的。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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