Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing

Wu, H.; Cui, K.; Zhu, B.; Lu, Y. W.; Sun, L.; Ma, Q.; Jian, A.; Hurtado, D. O.; Gao, X.; Li, Y.; Bhattacharjee, S.; Fu, H.; Birsner, A. E.; Malovichko, M.; Li, M.; Wang, B.; Singh, B.; Peng, Q.; Wong, S.; Norton, V.; Li, K. s.; Eisa-Beygi, S.; Wang, D.; Cowan, D. B.; Bielenberg, D. R.; Srivastava, S.; Rockowitz, S.; Xu, J.; D'Amato, R. J.; Chen, K.; Dong, M.; Biddinger, S.; Chen, H.

doi:10.1101/2023.12.04.569948

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bioRxiv · 10.1101/2023.12.04.569948

Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing

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Abstract

The forkhead box O1 (FOXO1) transcription factor plays critical roles in regulating not only metabolic activity but also angiogenesis in the vascular endothelium1-4. Our previous studies show that epsin endocytic adaptors can regulate both angiogenesis and lymphangiogenesis5-7. Endothelial cells (ECs) lining the inside of blood vessels are continuously exposed to circulating insulin and insulin-like growth factors (IGFs). Emerging evidences suggest that ECs can affect {beta}-cell function8-11. Excessive IGF2, especially elevated local IGF2 levels in islets, may represent a risk factor for developing diabetes12-15; however, the underlying molecular mechanisms by which aberrant angiogenesis and endothelium-derived factors regulate pancreatic {beta}-cell function in diabetes remain unclear. Here, we report that the pancreas of diabetic patients as well as the pancreas, skin, and plasma of streptozotocin/high fat diet (STZ/HFD)-induced diabetic mice and db/db mice contains excess IGF2, which can lead to {beta}-cell dysfunction and apoptosis. Single-cell transcriptomics combined with mass spectrometry analysis reveal that endothelial-specific knockout of FOXO1 increases circulating soluble and cell-membrane or intracellular expression levels of IGF type 2 receptor (IGF2R) and CCCTC-binding factor (CTCF), while decreasing IGF2 levels in diabetes. Both IGFR215-17 and CTCF18-21 can reduce IGF2 levels and may ameliorate {beta}-cell decline associated with excess IGF2 in diabetes. Furthermore, depletion of FOXO1, epsins, or knockdown of ULK1 inhibits autophagy formation in ECs, preventing degradation of vascular endothelial growth factor receptor 2 (VEGFR2) to promote angiogenesis and improve wound healing in diabetes. Our findings reveal that endothelial FOXO1 regulates epsin-dependent angiogenesis and affects {beta}-cell function and fate through CTCF and IGF2-IGF2R, providing a potential strategy for ameliorating diabetes and accelerating cutaneous wound healing.

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Wu, H., Cui, K., Zhu, B., Lu, Y. W., Sun, L., Ma, Q., Jian, A., Hurtado, D. O., Gao, X., Li, Y., Bhattacharjee, S., Fu, H., Birsner, A. E., Malovichko, M., Li, M., Wang, B., Singh, B., Peng, Q., Wong, S., Norton, V., Li, K. s., Eisa-Beygi, S., Wang, D., Cowan, D. B., Bielenberg, D. R., Srivastava, S., Rockowitz, S., Xu, J., D'Amato, R. J., Chen, K., Dong, M., Biddinger, S., Chen, H.. 2023-12-05. Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing. https://doi.org/10.1101/2023.12.04.569948

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