Effects of Mechanical Forces on the Biological Properties of Porcine Aortic Valve Leaflets

Abstract

Cardiac valves are dynamic, sophisticated structures which interact closely with the surrounding hemodynamic environment. Altered mechanical stresses, including pressure, shear and bending stresses, are believed to cause changes in valve biology, but the cellular and molecular events involved in these processes are not well characterized. Therefore, the overall goal of this project is to determine the effects of pressure and shear stress on porcine aortic valve leaflets biology. Results from the pressure study showed that elevated constant pressure (140 and 170 mmHg) causes significant increases in collagen synthesis. The increases were 37.5% and 90% for 140 and 170 mmHg, respectively. No significant differences in DNA and sGAG synthesis were observed under constant pressure. In the cyclic pressure study, the effects of both pressure magnitude and pulse frequency were studied. With the frequency fixed at 1.167 Hz, collagen and sGAG synthesis increased proportionally with mean pressure level. At a fixed pressure level (80-120 mmHg), collagen and sGAG synthesis were slightly increased by 25% and 14% at 0.5 Hz, respectively. DNA synthesis was significantly increased by 72% at 2 Hz. An experiment combining high magnitude (150-190 mmHg) and high frequency (2 Hz) demonstrated significant increases in collagen and sGAG synthesis (collagen: 74%, sGAG: 56%), but no significant changes in cell proliferation. Shear levels ranging from 1 to 80 dyne/cm2 were studied. Scanning electron microscopy results indicated that 48 hrs exposure to shear stress did not alter the circumferential alignment of endothelial cells. Collagen synthesis was significantly enhanced at 9 and 25 dyne/cm2, but not different from static controls under other shear conditions. Leaflets denuded of the endothelium were exposed to identical shear stress and showed very different responses. Collagen synthesis was not affected at any shear levels, but sGAG content was increased at shear of 9, 25 and 40 dyne/cm2. Further studies showed that the increases in collagen synthesis under pressure or shear stress was concurrent with a decline in the expression and activities of cathepsins L and S. This converse relationship between collagen synthesis and cathepsin activity indicated that cathepsins might be involved in valvular ECM remodeling.