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.