The Aryl Hydrocarbon Receptor--A New Role in Vascular Development

PI: Garet Lahvis and Christopher Bradfield
University of Wisconsin

Background: The aryl hydrocarbon (Ah) receptor was discovered in the 1970's and was found to regulate responses to a variety of environmental agents such as the polycyclic aromatic hyrdrocarbons found in cigarette smoke and the polychlorinated dioxin compounds found in industrial agents and the defoliant Agent Orange. When these chemicals bind to the receptor, the resulting comples interacts with another receptor known as the aryl hydrocarbon nuclear translocator (ARNT). This new complex then enters the nucleus of cells where it interacts with DNA and turns on a set of enzymes which in turn start to break down the chemicals and thus help to protect organisms once exposure has occurred.

More recent research has shown that the Ah receptor is expressed in a variety of tissues and at stages in development suggesting other roles for the receptor. Experiments using knock-out mice that have no copies of the gene coding for the Ah receptor provided evidence that the receptor was necessary for survival, growth, and reproduction. This study was undertaken to identify how the receptor might influence vertebrate development.

Advance: Mice without the Ah receptor were found to have livers about 25% smaller than normal mice. This finding was due to reduced blood flow to liver tissue by a process known as portosystemic shunting. The source of the shunt was determined to be the ductus venosus--a remnant of the fetal vascular system that had failed to close. Closer examinations of the mice determined that other fetal vascular structures were present in the eyes and kidneys.

Implication: These findings indicate the Ah receptor plays a very important role in regulating the development and maturation of the vascular structure in vertebrates. Given the receptor's known activity as a transcription factor, a likely mechanism for this effect is that the receptor is necessary for the regulation of genes involved in vascular remodeling and development. These experiments also suggest that health effects seen in response to dioxin and other exposures mediated by the Ah receptor may be as the result of perturbations in vascular development.

Reference: Lahvis, GP, Lindell, SL, Thomas, RS, McCuskey RS, Murphy C, Glover E, Bentx M, Southard J, Bradfield, CA. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. PNAS. 2000 Sept 12; 97(19):10442-47.