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 and biglycan as the major binding sites for LDL in the valve leaflet and renal ostia. Over the last year we have made the following progress: 1) Of the two major protein constituents of the plasma we have established that albumin, but not gamma globulin, is competitive with LDL for the decorin binding site using in vitro binding assays. This implies that albumin itself is shielding these proteoglycan site and, to some extent, preventing LDL binding in vivo. This added complication in developing a drug to block the interaction of LDL to the protoglycan site since it would need to be much more effective and albumin already is in occupying these sites. 2) We have initiated studies in atherosclerosis prone transgenic mice to correlate the development of the arterial macromolecular structures with LDL binding and fatty streak formation. We have developed the techniques to monitor the macromolecular structure development in the mouse using both in situ and in vitro methods. This is the first study of the development of the macromolecular structures of the arterial wall in a mammalian model. Studies are now underway in the disease model with different feeding regimes to stimulate atherosclerosis to evaluate the role of macromolecular structure development with atherosclerosis initiation in these animal models.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$216,239
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
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Zadrozny, Leah M; Neufeld, Edward B; Lucotte, Bertrand M et al. (2015) Study of the development of the mouse thoracic aorta three-dimensional macromolecular structure using two-photon microscopy. J Histochem Cytochem 63:8-21
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