Research Program

Synthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency, especially in small-vessel or low-flow applications, is limited. Smooth muscle cell accumulation and matrix deposition adjacent to the anastomoses may progress to intimal hyperplasia and graft failure. We have shown that smooth muscle cells on prosthetic grafts are characterized by a synthetic, proliferative phenotype that is distinctly different from the contractile phenotype of arterial smooth muscle cells. The graft smooth muscle cells produce high levels of growth factors, and this may stimulate the ongoing migration of arterial smooth muscle cells onto grafts as well as smooth muscle cell proliferation in the area of the anastomosis. In addition, the graft smooth muscle cells secrete higher levels of collagen than aortic smooth muscle cells. We are currently investigating the post-transcriptional regulation of matrix synthesis.

Prosthetic grafts in humans, unlike experimental animals, never develop a complete endothelial lining, and therefore, they remain relatively thrombogenic compared to normal blood vessels. Low density lipoprotein (LDL) oxidized by Dacron graft-activated monocytic cells inhibits EC migration in vitro, and the inhibition can be prevented by certain antioxidants. We are currently investigating the mechanism by which oxidized LDL inhibits endothelial cell migration, focusing on the effect of oxidized LDL on intracellular calcium concentration, cell membrane fluidity, and cytoskeleton. In addition, the effect of hypercholesterolemia, and the effect of antioxidants, on endothelial cell ingrowth onto prosthetic grafts in vivo is being studied. Identification of the mechanisms by which hypercholesterolemia impairs prosthetic graft healing will allow development of effective therapies to improve graft patency.

Active areas of investigation include: 1) the molecular mechanisms involved in the post-transcriptional regulation of collagen secretion by graft SMC, 2) the mechanism by which oxidized LDL inhibits endothelial cell migration, 3) and the effect of hypercholesterolemia on endothelial cell ingrowth onto prosthetic grafts in vivo . A better understanding of the changes in cell function on prosthetic grafts will be used to improve graft patency.