The Woodruff School

SUMMARY

The mechanical environment influences vascular smooth muscle cell (VSMC) functions related to the vascular remodeling. However, the relationships are not appropriately addressed by most mechanical models of arteries assuming homogeneity. Accounting for the effects of heterogeneity is expected to be important to our understanding of VSMC functions. We hypothesized that the distribution of mechanical stress and strain influences the localization of matrix metalloproteinase (MMP)-2 and -9 in situ. We developed a mathematical model of an arterial wall accounting for nonlinearity, residual strain, anisotropy, and structural heterogeneity. The distributions of elastin and collagen fibers, quantified using their optical properties, showed significant structural heterogeneity. Anisotropy was represented by the direction of collagen fibers, which was measured by the helical angle of VSMC nuclei. The recruiting points of collagen fibers were computed assuming the uniform strain of collagen fibers under physiological loading conditions. This was supported by observed uniform length and orientation of VSMC nuclei under physiological loading. The distributions of circumferential stresses computed using both heterogeneous and corresponding homogeneous models were correlated to the distributions of expression and activation of MMP-2 and -9 in porcine common carotid arteries, which were incubated in an ex vivo perfusion organ culture system under either normotensive or hypertensive conditions for 48 hours. While strains computed using incompressibility were identical in both models, the heterogeneous model, unlike the homogeneous model, predicted higher circumferential stresses in the outer layer. The tissue levels of MMP-2 and -9 were positively correlated to circumferential stresses computed using the heterogeneous model, which implies that areas of high stress are expected to be sites of localized remodeling. The results support the role of mechanical stress in vascular remodeling and suggest the importance of structural heterogeneity in studying mechanobiological responses.

SUBJECT:	Ph.D. Dissertation Defense

BY:	Yu-Shin Kim

TIME:	Thursday, June 28, 2007, 10:00 a.m.

PLACE:	MRDC Building, 4211

TITLE:	Correlation Between MMP-2 and -9 Levels and Local Stresses in Arteries Using a Heterogeneous Mechanical Model

COMMITTEE:	Dr. Raymond P. Vito, Chair (ME) Dr. Andr�s J. Garc�a (ME) Dr. Marc E. Levenston (ME) Dr. W. Robert Taylor (Medicine, Emory University) Dr. Zorina S. Galis (Eli Lilly and Company)

SUMMARY The mechanical environment influences vascular smooth muscle cell (VSMC) functions related to the vascular remodeling. However, the relationships are not appropriately addressed by most mechanical models of arteries assuming homogeneity. Accounting for the effects of heterogeneity is expected to be important to our understanding of VSMC functions. We hypothesized that the distribution of mechanical stress and strain influences the localization of matrix metalloproteinase (MMP)-2 and -9 in situ. We developed a mathematical model of an arterial wall accounting for nonlinearity, residual strain, anisotropy, and structural heterogeneity. The distributions of elastin and collagen fibers, quantified using their optical properties, showed significant structural heterogeneity. Anisotropy was represented by the direction of collagen fibers, which was measured by the helical angle of VSMC nuclei. The recruiting points of collagen fibers were computed assuming the uniform strain of collagen fibers under physiological loading conditions. This was supported by observed uniform length and orientation of VSMC nuclei under physiological loading. The distributions of circumferential stresses computed using both heterogeneous and corresponding homogeneous models were correlated to the distributions of expression and activation of MMP-2 and -9 in porcine common carotid arteries, which were incubated in an ex vivo perfusion organ culture system under either normotensive or hypertensive conditions for 48 hours. While strains computed using incompressibility were identical in both models, the heterogeneous model, unlike the homogeneous model, predicted higher circumferential stresses in the outer layer. The tissue levels of MMP-2 and -9 were positively correlated to circumferential stresses computed using the heterogeneous model, which implies that areas of high stress are expected to be sites of localized remodeling. The results support the role of mechanical stress in vascular remodeling and suggest the importance of structural heterogeneity in studying mechanobiological responses.