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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES013038-03
Application #
7036519
Study Section
Special Emphasis Panel (ZRG1-ENR (50))
Program Officer
Nadadur, Srikanth
Project Start
2004-05-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$147,452
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Chen, Zhenping; Xu, Ya; Bujalowski, Paul et al. (2015) N-(2-Aminoethyl) Ethanolamine-Induced Morphological, Biochemical, and Biophysical Alterations in Vascular Matrix Associated With Dissecting Aortic Aneurysm. Toxicol Sci 148:421-32
Xu, Ya; Treumann, Silke; Rossbacher, Roland et al. (2014) Dissecting aortic aneurysm induced by N-(2-aminoethyl) ethanolamine in rat: Role of defective collagen during development. Birth Defects Res A Clin Mol Teratol 100:924-33
Gong, Bin; Sun, Ju; Vargas, Grace et al. (2008) Nonlinear imaging study of extracellular matrix in chemical-induced, developmental dissecting aortic aneurysm: evidence for defective collagen type III. Birth Defects Res A Clin Mol Teratol 82:16-24
Gong, Bin; Boor, Paul J (2006) The role of amine oxidases in xenobiotic metabolism. Expert Opin Drug Metab Toxicol 2:559-71
Gong, Bin; Trent, Margaret B; Srivastava, Deepak et al. (2006) Chemical-induced, nonlethal, developmental model of dissecting aortic aneurysm. Birth Defects Res A Clin Mol Teratol 76:29-38
Boor, Paul J; Yang, Yonzhen; Gong, Bin (2006) Role of the media in vascular injury: atherosclerosis and dissection. Toxicol Pathol 34:33-8