Upregulation of the nonmuscle myosin light chain kinase (nmMLCK) might contribute to the development of pulmonary arterial hypertension (PAH), according to a new study published in the International Journal of Molecular Sciences.

“The data from this study is the first in our knowledge to recognize the importance of increased expression of nmMLCK contributing to endothelial cellular proliferation and migration with downstream activation of Ras/Raf/ERK pathway,” the researchers said. “nmMLCK is likely an important contributor to endothelial dysfunction recognized in PAH and may represent a unique therapeutic target.”

Molecular studies showed that nmMLCK and extracellular signal-regulated kinase (ERK) pathways, which regulate cytoskeleton dynamics, were activated in bone morphogenetic protein receptor 2 (BMPR2)-silenced human pulmonary artery endothelial cells. Loss-of-function mutations in BMPR2 and consequent attenuation of downstream signaling are observed in 80% of hereditable PAH.

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Inhibition of MLCK in BMPR2-silenced human pulmonary artery endothelial cells reduced cell viability, proliferation, and cytokine release, suggesting endothelial dysfunction. To inhibit MLCK, the researchers used ML-7, a specific inhibitor. The addition of the MLCK inhibitor to BMPR2-silenced human pulmonary artery endothelial cells allowed for a 50% decrease in cell viability and proliferation when compared with BMPR2 silencing alone. Moreover, MLCK inhibition decreased endothelial cell motility and migration.

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On the other hand, vascular endothelial growth factor-mediated upregulation of nmMLCK led to a hyperproliferative phenotype in human pulmonary artery endothelial cells, as well as increased cell migration. Vascular endothelial growth factor treatment increased the expression of the phosphorylated forms of MLCK and ERK.

The researchers recognized limitations to the selected study models, that is, the particular cells and cell models they on which they experimented. Future studies using relevant animal models and human tissues will be necessary to validate the role of nmMLCK in PAH pathobiology.


Anis M, Gonzales J, Halstrom R, et al. Non-muscle MLCK contributes to endothelial cell hyper-proliferation through the ERK pathway as a mechanism for vascular remodeling in pulmonary hypertension. Int J Mol Sci. 2022;23(21). doi:10.3390/ijms232113641