The proliferation and migration of vascular smooth muscle cells (VSMC) from the tunica media to the neointima are key events in the development and progression of atherosclerosis. We have recently shown that PDGF specifically stimulates proliferating VSMC, in culture, to secrete a 340-kDa glycan molecule which shares structural characteristics with hyaluronic acid (HA) and has a potent antiproliferative activity on VSMC. Studies on the migration of VSMC through an artificial basement membrane layer revealed that the 340-kDa HA molecule enhances VSMC migration towards PDGF. These results indicated that the 340-kDa HA may be involved in the processes associated with the formation of atherosclerotic lesions. The objectives of this proposal are: 1 ) to substantiate the involvement of glycans in the formation of atherosclerotic lesions by investigating possible quantitative and/or qualitative differences of the glycan molecules between human atherosclerotic arteries and arteries without atheromatosis (mammary artery), from the same patient; 2) to further investigate the molecular mechanism by which PDGF stimulates the secretion of the 340-kDa HA by VSMC and 3) to study the possible involvement of matrix metalloproteases (MMPs) during the 340-kDa HA-induced migration of VSMC.
The elucidation of the above questions will have a profound impact in the understanding of the cellular dysfunctions and the regulation of the local inflammatory responses involved in atherosclerosis.
The training objective will be to acquire research experience regarding: 1 ) the biochemistry of MMPs, glycans and growth factors in relation to atherosclerosis, and 2) techniques relevant to histopathological identification of atheromatic and physiological arteries, under the guidance of experienced scientists in the field.
There is no linkage of the project with industry.