Abstract 1702: Multimodality Imaging reveals Tgfβ Regulated Increase in MMP Protease Activity at Aneurysmal Lesions in Live Fibulin-4 Mice
Fibulins are a six-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures as elastic fibers and basement membranes. Previously, we generated mouse models underexpressing Fibulin-4 and showed that reduced expression of Fibulin-4 leads to aneurysm formation. Homozygous Fibulin-4 mice (Fibulin-4R/R) show dilatation of the ascending aorta and a tortuous and stiffened aorta, resulting from disorganized elastic fiber networks. In order to fully understand the complex nature of aortic vascular pathology in Fibulin-4R/R mice, we have used Gd-liposomes as an intravascular contrast agent to acquire high-resolution whole-body magnetic resonance (MR) angiograms on a 3.0T MR imaging scanner with a 4-channel phased array interface (8 cm field-of-view). Subsequent 3D MR angiographic reconstruction allowed accurate analysis of the thoraceous aortic aneurysmal (TAA) lesions in Fibulin-4R/R mice. We observed variations in size and location of TAA in ascending aorta of Fibulin-4R/R mice. Strikingly, we also noticed incidental cases of aortic coarctation, a type of aortic pathology that in humans is also associated with aneurysm formation. To examine whether the prominent perturbation of normal elastin lamellar structure in the Fibulin-4 mice arises from induction of TGFβ regulated MMP9, we performed molecular imaging of protease activity of MMPs. Using a protease-activatable near-infrared fluorescence (NIRF) probe, we monitored and quantified MMP upregulation in whole animals, and coregistered the fluorescence signal with CT images of the same animals. Subsequent isosurface concentration mapping from reconstructed tomographic images from Fibulin-4+/R and Fibulin-4R/R mice revealed a graded increase in activation of intravenously injectable MMP activatable NIRF probes within the aneurysmal lesions. In conclusion, we find combined manifestations of general aortic vascular pathology, including TAA, a tortuous descending aorta as well as aortic coarctation. Moreover, by tomographic non-invasive in vivo imaging methods we show that the defective dosage of a single gene (Fibulin-4) can determine the severity of aneurysm formation.