The Role of Leiomodin1 in Hypoxic Neovessel Maturation - PROJECT SUMMARY Peripheral artery disease (PAD) is a severe form of cardiovascular disease (CVD) affecting > 230 million individuals worldwide. Given the compelling evidence that PAD is a consequence of diminished blood flow in one or more major arteries of the limb, the expectation has been to develop therapies designed to stimulate the formation of new mature blood vessels to restore blood perfusion. However, despite years of investigations, the advent of medical therapies designed to improve blood perfusion to the distal limb have proven to be of limited benefit, due in large part to a lack of understanding of the underlying molecular mechanisms involved in the formation of mature neovessels. Interestingly, while pursuing the goals of an alternate proposal aimed at determining the role of Leiomodin 1 (LMOD1), a CVD genome wide association study target gene preferentially expressed in smooth muscle cells (SMCs), in the pathogenesis of atherosclerosis, this investigator led team found that mice with reduced Lmod1 expression demonstrate increased plaque hemorrhage owing to rupture of the neovasculature within the plaque. While this study illustrates the potential role of Lmod1 in the formation of mature neovessels, there is a need to investigate this association in the context of PAD. Accordingly, through this proposal the investigators seek to elucidate the relationship between Lmod1 and PAD. Specifically, they will determine the contribution and mechanism by which this gene regulates the vascular biology of SMC dependent formation of mature neovessels, an attribute that may be critical in regulating the pathogenesis of PAD. This proposal will bring together recognized experts from several fields to complement the translational studies and unique mouse models proposed to thoroughly understand the role of LMOD1 in PAD. In Aim 1, we will use cell culture models as well as state-of-the-art genomic and human translational approaches to elucidate the mechanistic pathway by which reduced LMOD1 mediates impaired neovessel maturation. In Aim 2, we will determine whether the LMOD1 mediated defect in neovessel maturation and ultimately PAD is predominantly mediated through SMCs by performing advanced in vivo survival surgeries on newly generated and available inducible SMC specific Lmod1 knockout mice and importantly investigate whether the defect can be rescued. In Aim 3, using in vitro and in vivo approaches we will investigate whether LMOD1-mediated defects in neovessel maturation may also account for increased pathogenesis of PAD in type 2 diabetes mellitus (T2DM), a strong risk factor of PAD. Taken together, this work will enhance the scientific community’s understanding on LMOD1 mediated formation of mature neovessels, a critical regulator of PAD. The proposed work is relevant to the mission of the NIH as it will lead to the development of new strategies and potential therapies to effectively treat patients diagnosed with PAD.
