Macromolecular Structure of Arterial Walls

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The arterial wall and arterial valves are complex macromolecular structures. One of the major elements of these structures is the scaffold that provides the strength and flexibility to perform the task in hand either retaining the blood in vessels against the arterial pressure or maintaining pressure via the function of coronary valves. In the last several years it has become apparent that the actual microstructure and composition of these macromolecules could influence the progress of different disease states most notably atherosclerosis and value calcification. To gain a better understanding of this process, we have embarked on studies to understand the fine structure of the macromolecules in arterial vascular bed using a novel optical imaging technique that relies on the non-linear excitation (NLE) of collagen and elastin to provide sub-micron images of their structure in unfixed fresh samples together with direct measures of low density lipoprotein particles (LDL) binding using fluorescence microscopy and conventional histology methods. These studies have identified Decorin as a major binding site for LDL in the valve leaflet. Over the last year we have made the following progress: 1) We are currently confirming our studies in the valve leaflet in the more general vascular bed using the renal artery ostia diverter we described two years ago. Protein samples for this vascular structure are being evaluated to establish whether a similar binding pattern discovered in the valves is in play in the peripheral vasculature. 2) Using our screening assay for LDL-Decorin binding, we have been evaluated several molecules for use in a pre-clinical screen in an atheroma prone mouse model. These studies will be designed to look for molecules that interfere with the LDL-Decorin interaction and then evaluate whether these molecules delay or inhibit atheroma formation in the mouse. Currently we have screened and rejected simple chondroitin sulfates and some homologs of heparin as being too low affinity for this purpose, though strong inhibion of binding can be demonstrated at high concentration. Currently we are evaluating several other candidate molecules to accomplish this task as well as evaluating the potential for conducting a more complete chemical screen of this interaction.