Related Experiment Video
Updated: Mar 2, 2026
Mouse Electroacupuncture Fixation Device Fabrication for Electroacupuncture Pretreatment in Diabetic Cardiomyopathy Mouse Model
Published on: April 18, 2025
Activation of thromboxane A2 receptors mediates endothelial dysfunction in diabetic mice
Xiaona Xie1,2, Wanchun Sun3, Jun Wang4
1a Central Laboratory , The Second Hospital of Jilin University , Changchun , P. R. China.
Background:
Diabetes is one of high-risk factors for cardiovascular disease. Improvement of endothelial dysfunction in diabetes reduces vascular complications. However, the underlying mechanism needs to be uncovered. This study was conducted to elucidate whether and how thromboxane A2 receptor (TPr) activation contributes to endothelial dysfunction in diabetes.
Methods And Results:
Exposure of human umbilical vein endothelial cells (HUVECs) to either TPr agonists, two structurally related thromboxane A2 (TxA2) mimetics, significantly reduced phosphorylations of endothelial nitric oxide synthase (eNOS) at Ser1177 and Akt at Ser473. These effects were abolished by pharmacological or genetic inhibitors of TPr. TPr-induced suppression of eNOS and Akt phosphorylation was accompanied by upregulation of PTEN (phosphatase and tension homolog deleted on chromosome 10) and Ser380/Thr382/383 PTEN phosphorylation. PTEN-specific siRNA restored Akt-eNOS signaling in the face of TPr activation. The small GTPase, Rho, was also activated by TPr stimulation, and pretreatment of HUVECs with Y27632, a Rho-associated kinase (ROCK) inhibitor, rescued TPr-impaired Akt-eNOS signaling. In mice, streptozotocin-induced diabetes was associated with aortic PTEN upregulation, PTEN-Ser380/Thr382/383 phosphorylation, and dephosphorylation of Akt (at Ser473) and eNOS (at Ser1177). Importantly, administration of TPr antagonist blocked these changes.
Conclusion:
We conclude that TPr activation impairs endothelial function by selectively inactivating the ROCK-PTEN-Akt-eNOS pathway in diabetic mice.
Insights
Thromboxane A2 receptor (TPr) activation impairs endothelial function in diabetes by inhibiting the ROCK-PTEN-Akt-eNOS pathway. Blocking TPr reverses these detrimental effects, offering a potential therapeutic target for diabetic vascular complications.
Area of Science:
- Cardiovascular Research
- Endothelial Biology
- Diabetic Complications
Background:
- Diabetes mellitus is a significant risk factor for cardiovascular disease.
- Endothelial dysfunction in diabetes contributes to vascular complications.
- The precise mechanisms underlying diabetic endothelial dysfunction require further elucidation.
Purpose of the Study:
- To investigate the role of thromboxane A2 receptor (TPr) activation in diabetic endothelial dysfunction.
- To determine the molecular pathways through which TPr activation affects endothelial cells.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) were exposed to TPr agonists.
- Pharmacological and genetic inhibitors of TPr, PTEN, and Rho-associated kinase (ROCK) were utilized.
- Streptozotocin-induced diabetic mouse models were employed.
- Western blotting and siRNA techniques assessed protein phosphorylation and signaling pathways.
Main Results:
- TPr activation reduced phosphorylation of endothelial nitric oxide synthase (eNOS) and Akt.
- TPr stimulation led to PTEN upregulation and increased PTEN phosphorylation, inhibiting Akt-eNOS signaling.
- Rho GTPase activation by TPr was observed, and ROCK inhibition restored eNOS/Akt signaling.
- In diabetic mice, TPr activation correlated with PTEN upregulation and reduced Akt/eNOS phosphorylation, effects reversed by TPr antagonist.
Conclusions:
- TPr activation significantly contributes to endothelial dysfunction in diabetes.
- The ROCK-PTEN-Akt-eNOS pathway is selectively inactivated by TPr activation in diabetic endothelial cells.
- Targeting TPr may offer a therapeutic strategy to mitigate vascular complications in diabetes.
