Suresh Athira, Kruse Kai, Arf Hendrik, Diéguez-Hurtado Rodrigo, Adams Ralf H
Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany.
Max Planck Institute for Molecular Biomedicine, Bioinformatics Service Unit, Münster, Germany.
Nat Commun. 2025 Jun 2;16(1):5108. doi: 10.1038/s41467-025-60105-9.
Engulfment and cell motility 2 (ELMO2) is a cytoskeletal adaptor protein necessary for cell migration and apoptotic cell removal. Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation (VMOS), a human disease involving progressive expansion of craniofacial bones in combination with anomalies in blood vessels that emerge from the external carotid artery, as well as aneurysms in the internal carotid artery. Here we show that global inactivation of Elmo2 in mice leads to midgestation embryonic lethality due to dilation of the 3 pharyngeal arch arteries and aneurysm formation in the common carotids. These vascular malformations are associated to defects in vascular smooth muscle cell organization and are phenocopied upon neural crest-specific deletion. In vitro experiments further confirm that ELMO2 regulates vascular smooth muscle cell adhesion, spreading and contractility through Rac1 activation and modulation of actin dynamics. Our findings provide new insights into the biological function of ELMO2 with relevant implications for understanding VMOS pathogenesis and raise the possibility of vessel-targeted diagnostic and treatment strategies.
吞噬与细胞运动蛋白2（ELMO2）是一种细胞骨架衔接蛋白，对细胞迁移和凋亡细胞清除至关重要。ELMO2功能丧失突变会导致骨内血管畸形（VMOS），这是一种人类疾病，涉及颅面骨的渐进性扩张，同时伴有源自颈外动脉的血管异常以及颈内动脉的动脉瘤。在此，我们表明小鼠中Elmo2的整体失活会导致妊娠中期胚胎致死，原因是第三咽弓动脉扩张和颈总动脉形成动脉瘤。这些血管畸形与血管平滑肌细胞组织缺陷有关，并且在神经嵴特异性缺失时会出现类似表型。体外实验进一步证实，ELMO2通过激活Rac1和调节肌动蛋白动力学来调节血管平滑肌细胞的黏附、铺展和收缩性。我们的研究结果为ELMO2的生物学功能提供了新的见解，对理解VMOS发病机制具有重要意义，并提高了血管靶向诊断和治疗策略的可能性。
