Control of vascular cell growth, differentiation, and injury response
Vascular disease is the greatest single cause of morbidity and mortality in developed societies. Understanding of the molecular mechanisms that control vascular smooth muscle cell (VSMC) proliferation, migration, and differentiation, central features in the pathogenesis of diseases such as atherosclerosis, restenosis after angioplasty, saphenous vein graft disease, and transplant-associated arteriosclerosis, remains incomplete.
We want to identify new factors and pathways that regulate these activities in VSMCs. The pathogenesis of vascular disease is complex: the factors that impinge on VSMCs are the result of reactivation of normal developmental pathways, contributions of inflammatory cells responding through both innate and acquired immune pathways, and response to altered blood flow and endothelial cell function in vessels damaged by both mechanical and biochemical stimuli. Our general approach has been to study the response to injury in rat and mouse models of specific vascular diseases.
As an example of reactivation, we have found that the protocadherin adhesion molecule Fat1 is induced in injured VSMC, and that it interacts with and limits the transcriptional activity of beta-catenin, the major downstream mediator of Wnt signaling. The Wnt pathway is a core developmental pathway that regulates many aspects of metazoan embryogenesis. Our data indicate that Fat1 may be an important regulator of VSMC growth in injured vessels.
We have also identified a role for colony stimulating factor-1 (CSF-1), the principal regulator of macrophage survival, proliferation, and differentiation, in control of transplant-associated arteriosclerosis, the major barrier to longterm success of organ transplants. Surprisingly, this effect appears to be mediated by VSMC-associated CSF-1 through an autocrine/juxtacrine mechanism that may not require macrophages.
Ongoing work in these areas involves defining precisely the molecular bases, from the cell surface to the nucleus, for these effects. By identifying novel mechanisms like these, we hope to find new targets for therapeutic intervention to regulate VSMC activities and improve vascular disease prevention and treatment.
Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE. The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. J Cell Biol. 2006 173(3):417-29.
Shungo Hiroyasu, Rong Hou, Liming Liu, Xu-ming Dai, E. R. Stanley, and Nicholas E. S. Sibinga. An autocrine/juxtacrine mechnism for Colony-Stimulating Factor-1-mediated smooth muscle cell proliferation in transplant arteriosclerosis. In preparation.