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.