The role of smooth muscle cell fluidization in the pathogenesis of pulmonary arterial hypertension
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During the progression of pulmonary arterial hypertension (PAH), the smooth muscle of the pulmonary artery changes phenotypically in several ways. Although many of these changes have been characterized, more remains to be understood about the mechanical properties of pulmonary arterial smooth muscle (PASM) cells and their role in PAH. To address this, PASM cells were studied using traction force microscopy to test their fluidization response to stretch, to determine if changes in contractility occur in the setting of PAH, and to screen a preliminary set of myosin inhibitors for those which relax the cell. As predicted, PASM cells produced a similar fluidization-resolidification response to transient stretch as shown in previous studies of other smooth muscle cell types. Although the statistical significance is not strong (p=0.082), PASM cells incubated in serum from PAH patients did show an increased average baseline contractility compared to cells treated with serum from normal volunteers. Of three myosin inhibitors tested, blebbistatin had a statistically significant (p=0.002) reduction in baseline contractility compared to untreated control cells. Taken together, these results support the hypothesis that stretch-induced fluidization is a feature of the normal PASM cell and suggest that factors in the PAH milieu may cause changes in the PASM cell, yielding a more contractile phenotype. A possible avenue for treating PAH may lie in using myosin inhibitor drugs such as blebbistatin to reduce contractility of the PASM cell.