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

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.