Abstract
Diabetes is one of high risk factors for cardio- and cerebra-vascular diseases, including stroke, atherosclerosis and hypertension. This study was conducted to elucidate whether and how thromboxane receptor (TPr) activation contributes to blood-brain barrier (BBB) dysfunction in diabetes. Human brain microvascular endothelial cells (HBMECs) were cultured. The levels of phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 (p-eNOS) and Akt at Ser473 (p-Akt) were assayed by western blot. Exposure of HBMECs to either high glucose (HG) or thromboxane A2 (TxA2) mimetic U46619, significantly reduced p-eNOS and p-Akt. These effects were abolished by pharmacological or genetic inhibitors of TPr. HG/U46619-induced suppressions of eNOS and Akt phosphorylation were accompanied by upregulation of PTEN and Ser380/Thr382/383 PTEN phosphorylation. PTEN-specific siRNA restored Akt-eNOS signaling in the face of TPr activation or HG. The small GTPase, Rho, was also activated by HG stimulation, and pretreatment of HBMECs with Y27632, a Rho-associated kinase (ROCK) inhibitor, rescued HG-impaired Akt-eNOS signaling. In STZ-injected rats, we found that hyperglycemia dramatically increased the levels of PTEN and PTEN-Ser380/Thr382/383 phosphorylation, reduced both levels of p-eNOS and p-Akt, and disrupted BBB function assayed by Evans blue staining, which were abolished by SQ29548 treatment. We conclude that hyperglycemia activates thromboxane A2 receptor to impair the integrity and function of blood-brain barrier via the ROCK-PTEN-Akt-eNOS pathway.
Highlights
Diabetes mellitus is usually associated with the development of cardio- and cerebra-vascular diseases, including stroke, atherosclerosis and hypertension, which is characterized by endothelial dysfunction [1,2,3,4]
In STZ-injected rats, we found that hyperglycemia dramatically increased the levels of PTEN and PTEN-Ser380/ Thr382/383 phosphorylation, reduced both levels of p-endothelial nitric oxide synthase (eNOS) and p-Akt, and disrupted blood-brain barrier (BBB) function assayed by Evans blue staining, which were abolished by SQ29548 treatment
We have for the first time provided evidences that hyperglycemia via thromboxane receptor (TPr) activation induces BBB dysfunction in vitro and in vivo
Summary
Diabetes mellitus is usually associated with the development of cardio- and cerebra-vascular diseases, including stroke, atherosclerosis and hypertension, which is characterized by endothelial dysfunction [1,2,3,4]. Prostanoids have critical roles in the development of endothelial dysfunction [5]. Thromboxane A2 (TxA2) perturbs the normal quiescent phenotype of endothelial cells. TxA2 binds to the thromboxane A2 receptor (TPr), activation of which is implicated in atherosclerosis and inflammation [6, 7]. TPr activation induces endothelial cells apoptosis by inhibiting Akt phosphorylation [9]. TPr activation inhibits vascular www.impactjournals.com/oncotarget endothelial growth factor-induced endothelial cells migration and angiogenesis by decreasing Akt and eNOS phosphorylation [10]
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