Fetal Basis of Dissecting Aortic Aneurysm

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DESCRIPTION (provided by applicant): Dissecting aortic aneurysm (DAA) is the sudden tearing or splitting of the medial layers of the aorta, usually beginning in its thoracic portion, and extending distally through its branches. A frequent cause of sudden death in Marfan's syndrome, DAA also occurs as an isolated event, and is associated with pregnancy. In recent experiments, we found that by exposing timed-pregnant rats (on days 14-21 of gestation) to nontoxic doses of semicarbazide, an inhibitor of the vascular enzyme semicarbazide-sensitive amine oxidase (SSAO), newborn rats develop classic DAA immediately after birth. To our knowledge, this is the first experimental model of environmentally induced, developmental DAA. We hypothesize that SSAO-inhibition during development results in biochemical, biophysical, and genetic aberrations in the cellular production of critical extracellular matriceal (structural) proteins, especially the elastin-complex, with resultant weakening of the vascular wall. In this new experimental model, we will focus on the fetal rat, the day before birth, to uncover the changes in matrix milieu that predispose to DAA. As a first Specific Aim, the biochemical aberrations in aortic structural components will be defined. Biophysical properties of single pathologic matrix molecules (e.g., elastin-complex) will be compared to normal using the exciting new technique of atomic-force-microscopy. With gene microarray techniques, genetic alterations that precede DAA will be revealed. Then, as a second Specific Aim, mechanistic experiments in vascular smooth muscle cells cultured from the same fetal rats will probe how genetic alterations drive the changes in aortic extracellular matrix milieu to result in vascular weakening, and dissection.