The biology and targeting of Smooth Muscle Cells for translational approaches in Vascular Disease

Smooth muscle cells (SMCs) have a central role in most vascular disorders such as atherosclerotic plaque rupture that is the major cause of myocardial infarction and stroke, aortic aneurysm and rupture, but also restenosis after vascular reconstructions where endovascular stent implantation induces mechanical damage and neointimal growth. Overall, vulnerable vascular lesions are featured by enhanced inflammation, tissue degradation and depletion of smooth muscle cells (SMCs) and we still lack understanding of the mechanisms that drive these processes.

Given the capacity of SMCs to provide tissue integrity and retain lesion stability, I propose to explore the mechanisms that regulate their function in vascular biology, remodelling and disease.

I postulated that phenotypes of patients with atherosclerosis correlate with specific molecular patterns and organized a hypothesis-generating workflow based on deep molecular profiling of plaque tissue and plasma from a biobank of >1300 patients undergoing surgery for carotid atherosclerosis. A biobank of >600 patients undergoing surgery for aortic aneurysms is also available for the study, along with molecular tissue profiles.

Identified candidates are further explored in experimental studies using animal models of vascular remodelling and disease, ex vivo and in vitro systems. SMC-related candidates with translational potential are validated in independent human cardiovascular cohorts where their value for risk prediction and targeted molecular diagnostics is evaluated.

With this integrative approach, we found a number of novel molecular signatures and pathways that characterise the various phenotypic state(s) of SMCs in vascular disease, particularly in relation to SMCs differentiation, de-differentiation, trans-differentiation and survival in atherosclerotic plaques and other vascular lesions. These novel markers improve our understanding of the much-debated plasticity of SMCs in vascular disease, as well as their phenotypic definition, and are related to their role in plaque vulnerability, ultimately with therapeutic or diagnostic potential.

Full understanding of the various mechanisms that regulate phenotype, function and balance between apoptosis and survival of SMCs in vascular biology and pathology can yield new strategies to prevent complications of end-stage vascular disease.