Chemical-induced, nonlethal, developmental model of dissecting aortic aneurysm

Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):29-38. doi: 10.1002/bdra.20222.

Abstract

Background: A chemical-induced, nonlethal, dissecting aortic aneurysm (DAA) is described following in utero exposure to semicarbazide, an inhibitor of the vascular enzyme semicarbazide sensitive amine oxidase (SSAO).

Methods: Sprague-Dawley rat dams were given semicarbazide (0.096-49.000 mg/kg/day) by IP injection on gestation days (GDs) 14-20, a period of rapid aortic development. Newborn rats (day 1) were killed and their thoracic organs were removed en bloc for near-serial cross sections and routine histopathology, Movat stain for elastin, and immunohistochemistry to differentiate cells involved in the evolution of the DAA. In subsequent experiments, pups from treated dams (0.096-6.125 mg/kg/day) were allowed to survive for 7 or 28 days.

Results: DAA occurred in nearly 100% of the rats at all doses except the lowest tested (1.530, 0.096 mg/kg/day). Dissections frequently extended to the carotids and, less frequently, to the abdominal aorta. Remodeling of vascular lesions proceeded by organization of collections of blood in vascular media (the "false lumen"), proliferation of vascular smooth muscle cells, fibrosis, and formation of irregular frayed elastic lamellae in healed vascular media. Biochemical quantitation and Western blot analysis of main extracellular matrix proteins on GD 20 showed no overt difference in expression of collagen type I, fibrillin-1, or elastin.

Conclusion: This developmental model provides investigators an opportunity to explore the pathologic mechanisms of DAA and to examine the potential long-term effects of vascular remodeling of DAA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors
  • Analysis of Variance
  • Aneurysm, Dissecting / chemically induced*
  • Aneurysm, Dissecting / enzymology
  • Aneurysm, Dissecting / metabolism
  • Aneurysm, Dissecting / pathology
  • Animals
  • Animals, Newborn
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / enzymology
  • Aorta, Thoracic / growth & development
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / chemically induced*
  • Aortic Aneurysm, Thoracic / enzymology
  • Aortic Aneurysm, Thoracic / metabolism
  • Aortic Aneurysm, Thoracic / pathology
  • Collagen / analysis
  • Collagen / metabolism
  • Dose-Response Relationship, Drug
  • Elastin / analysis
  • Elastin / metabolism
  • Female
  • Gestational Age
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Models, Biological*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Semicarbazides / administration & dosage
  • Semicarbazides / toxicity*

Substances

  • Semicarbazides
  • carbamylhydrazine
  • Collagen
  • Elastin
  • Amine Oxidase (Copper-Containing)