ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2023; 19(6):1910-1924. doi:10.7150/ijbs.82855 This issue Cite
Research Paper
SCF/c-Kit-activated signaling and angiogenesis require Gαi1 and Gαi3
1. Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou, China.
2. The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
3. Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
4. Vascular Surgery Department, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, China.
5. Department of Otorhinolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, China.
# Equal contributors.
Abstract
The stem cell factor (SCF) binds to c-Kit in endothelial cells, thus activating downstream signaling and angiogenesis. Herein, we examined the role of G protein subunit alpha inhibitory (Gαi) proteins in this process. In MEFs and HUVECs, Gαi1/3 was associated with SCF-activated c-Kit, promoting c-Kit endocytosis, and binding of key adaptor proteins, subsequently transducing downstream signaling. SCF-induced Akt-mTOR and Erk activation was robustly attenuated by Gαi1/3 silencing or knockout (KO), or due to dominant negative mutations but was strengthened substantially following ectopic overexpression of Gαi1/3. SCF-induced HUVEC proliferation, migration, and capillary tube formation were suppressed after Gαi1/3 silencing or KO, or due to dominant negative mutations. In vivo, endothelial knockdown of Gαi1/3 by intravitreous injection of endothelial-specific shRNA adeno-associated virus (AAV) potently reduced SCF-induced signaling and retinal angiogenesis in mice. Moreover, mRNA and protein expressions of SCF increased significantly in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. SCF silencing, through intravitreous injection of SCF shRNA AAV, inhibited pathological retinal angiogenesis and degeneration of retinal ganglion cells in DR mice. Finally, the expression of SCF and c-Kit increased in proliferative retinal tissues of human patients with proliferative DR. Taken together, Gαi1/3 mediate SCF/c-Kit-activated signaling and angiogenesis.
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