CRY2 activates the IGF2/PI3K/AKT signaling to inhibit the blood-brain barrier disruption in chronic cerebral hypoperfusion

Cryptochrome 2 (CRY2) has been implicated in blood perfusion recovery. This study aims to explore its effects on the repair of the blood-brain barrier (BBB) during chronic cerebral hypoperfusion (CCH). Human cortical microvessels endothelial cells/D3 (hCMEC/D3) are induced with hypoxia and co-cultured with microvascular pericytes and astrocytes.

Mice are induced by bilateral common carotid artery stenosis (BCAS). In hypoxia-induced hCMEC/D3 cells and vascular endothelial cells from BCAS-induced mice, CRY2 is downregulated. CRY2 overexpression ameliorates hCMEC/D3 injury and inhibits BBB disruption and cognitive dysfunction in mice. rs10838524 (A > G) resulted in the CRY2 reduction and correlated with more severe CCH.

CRY2 mediates the time-dependent expression of insulin-like growth factor 2 (IGF2). The ameliorative effect of CRY2 on CCH is dependent on the IGF2/Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (AKT). The findings demonstrate that the rs10838524 (A > G) of CRY2 represses enhancer-mediated transcription of CRY2, thereby attenuating activation of IGF2 and impairing PI3K/AKT signaling.

This work was supported by the National Natural Science Foundation of China (Grant No. 82571356). These authors contributed equally: Mingli He, Cheng Yang, Haiyuan Shi. Department of Neurology, Affiliated Lianyungang Hospital, Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang, P.R.

China Mingli He, Cheng Yang, Haiyuan Shi & Xunrong Xuan Department of Neurology, Lianyungang Clinical Medical College, Nanjing Medical University, Lianyungang, P.R. China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.