Gene regulation in Cardiovascular Remodelling and Inflammation

Many important biological processes, including the regulation and development of the immune and cardiovascular systems, are regulated by the calcineurin (CN)/NFAT pathway. Much of our previous work relates to molecular interactions of CN with substrates. We are now studying the regulation and function of this pathway in inflammation, cardiovascular and inflammatory diseases.

Our work on angiogenesis addresses the regulation of CN in endothelial cells by VEGF. We use retinopathy of prematurity as a model of the mechanisms of neovessel formation in ischemic retinopathies, using lentiviral vectors to identify potential therapeutic targets.

We are also analyzing gene expression triggered by angiotensin II (AngII) in cardiomyocytes and vascular smooth muscle (VSM). This work is aimed at identifying molecular mediators of cardiac hypertrophy. We have found several genes regulated by CN in two mouse models of cardiac hypertrophy and plan to characterize their roles in this pathology.

Through in vivo infection with lentiviral vectors encoding motifs important for CN-NFAT interactions, we can prevent or retard the development of arthritis in mice. In our system, inflammation is curtailed by the infection in vivo of macrophages at distinct locations and the subsequent migration of these cells to inflammation sites.

We are dissecting signaling pathways involved in vascular wall remodeling, a major feature of vascular diseases such as atherosclerosis, aneurysm and restenosis. We have set up animal models of these pathologies, and have generated mice deficient for AngII-target molecules that are regulated by CN. Some of these animals are totally resistant to these diseases and we are working to elucidate the molecular and cellular mechanisms underlying this protection.

Figure 1. Confocal microscopy merged images of Rcan1 (red) and SMA (green) immunostaining and nuclear staining (blue) of abdominal aortic cross-sections from either saline (image 1) or AngII-treated (image 2) Apoe-/-mice. Images are maximal projections of a complete z-series.

Figure 2. Cross-sections of uninjured and injured mouse femoral arteries stained with hematoxilin-eosin (H&E) and Van Gieson’s stain (VG).