2. Academic Validation
  3. KCNK2-mediated regulation of MMP-2/9 by PlGF influences uterine artery function in pregnancy-induced hypertension

KCNK2-mediated regulation of MMP-2/9 by PlGF influences uterine artery function in pregnancy-induced hypertension

  • BMC Pregnancy Childbirth. 2025 Jun 2;25(1):646. doi: 10.1186/s12884-025-07743-5.
Yinzhen Chen # 1,  Mingfu Chen # 1,  Ridong Zhou 2,  Jichang Zheng 2,  Gongxin Yang 2,  Meiyu Chen 1,  Jing Tu 2,  Hongming Lin 2,  Hu Zhao 1 2 3 4,  Chen Lin 5 6 7 8,  Xiaobin Chen 9 10 11 12
Affiliations

Affiliations

  • 1 Department of General Surgery, Fuzong Teaching Hospital of Fujian University of Traditional Chinese Medicine (900th, Hospital), Fuzhou, 156 Xierhuan Northern Road, Fujian, 350025, China.
  • 2 Department of General Surgery, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350025, China.
  • 3 Department of General Surgery, Dongfang Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, Fujian, 350025, China.
  • 4 Department of General Surgery, 900th, Hospital of PLA Joint Logistic Support Force, Fuzhou, Fujian, 350025, China.
  • 5 Department of General Surgery, Fuzong Teaching Hospital of Fujian University of Traditional Chinese Medicine (900th, Hospital), Fuzhou, 156 Xierhuan Northern Road, Fujian, 350025, China. chenlin.med@hotmail.com.
  • 6 Department of General Surgery, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350025, China. chenlin.med@hotmail.com.
  • 7 Department of General Surgery, Dongfang Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, Fujian, 350025, China. chenlin.med@hotmail.com.
  • 8 Department of General Surgery, 900th, Hospital of PLA Joint Logistic Support Force, Fuzhou, Fujian, 350025, China. chenlin.med@hotmail.com.
  • 9 Department of General Surgery, Fuzong Teaching Hospital of Fujian University of Traditional Chinese Medicine (900th, Hospital), Fuzhou, 156 Xierhuan Northern Road, Fujian, 350025, China. cxb104189@126.com.
  • 10 Department of General Surgery, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350025, China. cxb104189@126.com.
  • 11 Department of General Surgery, Dongfang Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, Fujian, 350025, China. cxb104189@126.com.
  • 12 Department of General Surgery, 900th, Hospital of PLA Joint Logistic Support Force, Fuzhou, Fujian, 350025, China. cxb104189@126.com.
  • # Contributed equally.
PMID: 40457264 DOI: 10.1186/s12884-025-07743-5
Abstract

Background: Pregnancy induced hypertension (PIH) is characterized by aberrant uterine arterial remodeling, a process tightly associated with an imbalance between placental growth factor (PLGF) and soluble fms like tyrosine kinase 1 (sFlt 1) as well as the down regulation of Matrix Metalloproteinases 2/9 (MMP 2/9). This study investigated the regulatory effect of PLGF on the two pore domain Potassium Channel KCNK2 and its downstream targets MMP 2/9, and explored the role of the PLGF KCNK2 MMP 2/9 axis in PIH related uterine arterial dysfunction.

Methods: In vitro, human aortic endothelial cells (HAECs) were assessed for proliferation and migration using CCK 8 and Transwell assays. Nitric oxide (NO) and endothelin 1 (ET 1) levels were quantified by ELISA, while KCNK2 and MMP 2/9 expression was analyzed by Western blotting. In vivo, a Sprague Dawley rat PIH model was established to monitor blood pressure and 24 h urinary protein. Hematoxylin-eosin staining was used to measure uterine arterial intimal thickness; endothelial nitric oxide synthase (eNOS) and ET 1 localization was determined by immunohistochemistry, and KCNK2 as well as MMP 2/9 expression was quantified by immunohistochemistry and Western blotting.

Results: 2,2,2 Trichloroethanol and PLGF significantly enhanced endothelial cell proliferation and migration, increased NO, decreased ET 1, and up regulated KCNK2 and MMP 2/9 expression (P < 0.05); ropivacaine produced opposite effects. PIH rats exhibited markedly elevated blood pressure and urinary protein, intimal thickening, reduced eNOS and elevated ET 1, together with diminished MMP 2/9 expression. Combined treatment with PLGF and 2,2,2 trichloroethanol lowered blood pressure and urinary protein, attenuated intimal thickness, increased eNOS and decreased ET 1, and up regulated KCNK2 and MMP 2/9 (P < 0.05).

Conclusion: 2,2,2 Trichloroethanol activates KCNK2, elevates MMP 2/9, and improves uterine arterial endothelial function, while PLGF synergizes with KCNK2 signaling to potentiate these effects. The PLGF KCNK2 MMP 2/9 axis plays a pivotal regulatory role in the vascular pathology of PIH, highlighting its potential as a therapeutic target for PIH related vascular dysfunction.

Keywords

KCNK2; Matrix metalloproteinases (MMP-2/9); Placental growth factor (PlGF); Pregnancy-induced hypertension (PIH); Uterine artery.

Figures
Products