Hypoglycemia is a common and serious problem among patients with
type 1 diabetes receiving treatment with
insulin. Clinical studies have demonstrated that
hypoglycemic edema is involved in the initiation of
hypoglycemic brain damage. However, the mechanisms of this
edema are poorly understood.
Vascular endothelial growth factor (
VEGF), a potent regulator of blood vessel function, has been observed an important candidate
hormone induced by
hypoglycemia to protect neurons by restoring plasma
glucose. Whether
VEGF has a protective effect against
hypoglycemia-induced damage in brain endothelial cells is still unknown. To investigate the effects of
hypoglycemia on cerebral microvascular endothelial cells and assess the protective effect of exogenous
VEGF on endothelial cells during
hypoglycemia, confluent monolayers of the brain endothelial cell line bEnd.3 were treated with normal (5.5 mM
glucose),
hypoglycemic (0, 0.5, 1 mM
glucose) medium or
hypoglycemic medium in the presence of
VEGF. The results clearly showed that
hypoglycemia significantly downregulated the expression of
claudin-5 in bEnd.3 cells, without affecting ZO-1 and
occludin expression and distribution. Besides, transendothelial permeability significantly increased under
hypoglycemic conditions compared to that under control conditions. Moreover, the
hypoglycemic medium in presence of
VEGF decreased endothelial permeability via the inhibition of
claudin-5 degradation and improved
hypoglycemia-induced cell toxicity. Furthermore,
Glucose transporter-1 (Glut-1) and apoptosis regulator Bcl-2 expression were significantly upregulated. Taken together,
hypoglycemia can significantly increase paraendocellular permeability by downregulating
claudin-5 expression. We further showed that
VEGF protected brain endothelial cells against
hypoglycemia by enhancing
glucose passage, reducing endothelial cell death, and ameliorating paraendocellular permeability.