Exploring the Biochemistry of Aortic Aneurysm Formation
An aneurysm is a weakened section of a major blood vessel that expands and grows into a balloon-like structure. Rupture is often fatal. Aneurysms tend to form in specific locations, and researchers here ask why this is the case. Associating a characteristic set of changes in cell biochemistry with the formation of aneurysms in mice is a first step on a long road towards better detailed understanding of the mechanisms involved, and the development of interventions to prevent formation of aneurysms.
A vascular dilatation in the aorta can be life-threatening if it bursts. These so-called aortic aneurysms typically form in the same sites of the large blood vessel: either on the upper arch or in the abdominal cavity. In order to find out what distinguishes the repeatedly affected vascular regions from others, researchers developed a method to specifically examine the endothelium of the aorta: the innermost layer of the blood vessel. "We know from other vascular diseases such as arteriosclerosis that there are changes in this innermost layer long before symptoms appear."
The researchers analyzed the gene activity at different sites of the aorta and compared the sites where aneurysms frequently form with those that don't show this tendency. "We identified certain patterns of upregulated genes in the sites where dilatations frequently form. These remarkably active genes affect, for example, changes in the extracellular matrix, the formation of new blood vessels and some inflammatory reactions." Such genetic abnormalities are also found in tissue from human aneurysms. The researchers also determined the stiffness of the endothelium in the healthy aortic samples. The less elastic the endothelium, the more detrimental it is to vascular health. They proved that the endothelium was stiffer in the sites where aneurysms frequently develop than in the control areas.
The team used an established model of a knock-out mouse that tends to form aneurysms due to a targeted genetic modification. If high blood pressure is additionally induced in these mice, aortic aneurysms form. They compared the genetic activity in the aortic endothelium of the genetically modified mice without aneurysm with that of mice that had developed an aneurysm due to added high blood pressure. "In the mice with aneurysms, we found a much greater degree of gene alterations that belong to the same category as the gene alterations in healthy mice. In the mice with an aneurysm, the vessel wall was also altered." The researchers conclude that the sites where aneurysms frequently form are weak points from the outset. We don't know exactly why this happens - perhaps it has to do with the mechanical conditions and the blood flow there, or perhaps the altered gene activity at these sites is inherited from birth." The latter seems plausible, as the aorta develops at different heights from different embryonic precursor cells.