Vascular
disease, the greatest single cause of morbidity and mortality in developed
societies, results from interactions between circulating inflammatory cells,
the endothelium that lines the vasculature, underlying vascular smooth muscle
cells (VSMCs) that comprise most of the arterial wall, and stem/progenitor
cells found in the surrounding adventitia. The underlying pathogenesis is
complex: factors that impinge on these cell types include reactivated
developmental pathways, innate and acquired immune responses, and changes in
cell function that result from physical stresses, perturbed blood flow, and
biochemical stimuli. Our general approach is to characterize these responses at
the molecular level, in cell culture, and in mouse models that reflect specific
types of vascular injury, including atherosclerosis, mechanical trauma, and
transplant-associated arteriosclerosis.
In Drosophila, Fat proteins are important regulators of cell
growth and planar cell polarity. We have linked the atypical cadherin adhesion
molecule Fat1 to significant effects on mammalian vascular remodeling. Our
studies in mammalian VSMCs show that Fat1 interacts with beta-catenin to limit
canonical Wnt signaling, a core developmental pathway that regulates many
aspects of metazoan embryogenesis, and with Atrophin proteins to control VSMC
directional migration. Recent findings suggest that Fat1 is an important
regulator of VSMC growth and differentiation in injured vessels, and ongoing
studies aim to understand the intracellular and extracellular signals that
emanate from Fat1 in cis- and trans-signaling modes. Direct studies of
beta-catenin indicate that its expression in VSMCs is required for vascular
formation in development and important in adult arterial injury response.
Current efforts to understand beta-catenin’s essential function in these
settings are underway.
Diabetes and obesity are important risk factors for cardiovascular
disease. We are investigating how allograft inflammatory factor-1 (Aif-1), a 17
kD Ca2+-binding protein contributes to these conditions. Specific Aif-1
isoform-dependent functions that underlie effects on macrophage migration,
phagocytosis, survival, and inflammatory signaling are subjects of ongoing
studies.
Finally, in collaborative work with the Stanley lab, we have
characterized a role for colony stimulating factor-1 (CSF-1), the main
regulator of macrophage survival, proliferation, and differentiation, in
control of transplant-associated arteriosclerosis, the major barrier to
long-term success of organ transplants. Surprisingly, this effect appears to
involve VSMC-associated CSF-1 in an autocrine/juxtacrine mechanism that is
largely independent of macrophages.
Ongoing work in these areas involves defining the molecular
bases for these observations. By identifying such novel mechanisms, we hope to
find new targets for therapeutic intervention to regulate vascular cell
activities and improve related disease prevention and treatment.
