| First Author | Shi D | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 11 | Pages | 2665-2677 |
| PubMed ID | 30354240 | Mgi Jnum | J:285108 |
| Mgi Id | MGI:6385411 | Doi | 10.1161/ATVBAHA.118.311538 |
| Citation | Shi D, et al. (2018) Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis. Arterioscler Thromb Vasc Biol 38(11):2665-2677 |
| abstractText | Objective- Mitochondria are the important yet most underutilized target for cardio-cerebrovascular function integrity and disorders. The Tom (translocases of outer membrane) complex are the critical determinant of mitochondrial homeostasis for making organs acclimate physiological and pathological insults; however, their roles in the vascular system remain unknown. Approach and Results- A combination of studies in the vascular-specific transgenic zebrafish and genetically engineered mice was conducted. Vascular casting and imaging, endothelial angiogenesis, and mitochondrial protein import were performed to dissect potential mechanisms. A loss-of-function genetic screening in zebrafish identified that selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities. Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function. Mechanistically, Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling, which incurred angiogenic impairment that underlies cerebrovascular network malformation. Conclusions- Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium. |
