The mice carried a marker gene, beta galactosidase, that turns tissues blue. Different strains of the mice had different fragments of the MMP2 gene coupled to the so-called blue gene. Leg muscles turned blue only in the strain of mice with the specific gene fragment that turns on in response to arterial blockage.
In this way, the researchers identified and described previously unknown areas of the MMP2 gene, plus other molecules that activate those areas, that are essential to expression of the gene in response to decreased blood flow.
"It's a very time-consuming approach, but a very elegant way to deal with the problem," comments Sarkar. "This paper is a very fundamental examination of the mechanisms involved in gene regulation in the growth of arteries." The next research step, according to Sarkar, will be to carry out the same experiments in animal models of the various conditions known to cause vascular disease: cigarette smoking, high cholesterol, diabetes, and hypertension.
"For each of these models we will ask, one, is expression of MMP2 impaired, and two, if there is less arterial growth," Sarkar says. "Then if both of those are true ?and we think they will be ?then we can identify the mechanisms by which expression of MMP2 is blocked."
Over the long term, Sarkar plans to study the same genetic mechanisms in humans, "perhaps in tissue samples taken from patients at the time of surgery." He hopes that eventually, his research will lead to new clinical treatments for arterial blockage in patients.
"As a vascular surgeon, I take care of people who have problems with poor blood flow to different parts of their bodies," he notes. "One thing we know for sure: our patients do not grow new arteries, and that's why I have to operate on them."
Other co-authors o
Source:University of California - San Francisco