Role Of The Microtubule Network In Right Ventricle Passive Viscoelasticity With Pulmonary Hypertension Development

Microtubule (MT) polymerization is a key contributor to myocardium viscoelasticity, which describes elastic and viscous resistance under stress and impacts the contractile function. MT de- or hyper-polymerization has been shown to decrease or increase healthy cardiomyocyte viscoelasticity, but the responses of hypertrophied cells to these modifications are unknown. Moreover, the ventricular free wall is a complex tissue composed of myofibers, collagen and vasculature, and it exhibits anisotropic mechanical behavior. To fully understand the role of MT in the tissue-level anisotropic viscoelasticity of myocardium, we investigated the responses of healthy and failing rat right ventricles (RV) to alterations in MT network. All procedures were approved by Colorado State University IACUC. Adult male rats were treated with monocrotaline to induce pulmonary hypertension and RV failure. After euthanasia, the RV free wall underwent equibiaxial stress relaxation in intact state (baseline) and under the treatment of colchicine and deuterium oxide (D 2 O) to remove and enhance MT network, respectively. Viscoelastic parameters were quantified as previously described. As expected, the diseased RV had greater viscoelasticity than the healthy RV. Depolymerization of MT in healthy RVs reduced tissue viscosity (relaxation rate) and elasticity (relaxation modulus), and the changes were more significant in the longitudinal (outflow tract) direction. MT hyper-polymerization increased tissue elasticity and decreased viscosity, with the changes stronger in the circumferential direction. In diseased RVs, MT depolymerization reduced viscosity in both directions and elasticity only in the circumferential direction. However, MT hyper-polymerization unexpectedly decreased tissue elasticity and tended to decrease viscosity, as well. The altered MT polymerization dynamics after D 2 O treatment in a fibrotic environment may explain these heterogeneous responses This is the first report of distinct impacts of MT polymerization on the tissue mechanical behavior between the hypertrophied and healthy myocardium. The exact molecular mechanisms involving MT polymerization dynamics and the interactions with collagen await further investigation.