BioWorld International Correspondent
LONDON - Italian researchers have identified a novel signaling pathway that helps to control blood pressure and could pave the way for the development of a new generation of hypertension drugs.
Stefano Piccolo, associate professor of embryology at the University of Padua in Italy, told BioWorld International: "Our discovery goes right to the roots of the pathology of hypertension. We have identified a well-defined defect that leads to excessive levels of a growth factor. These high levels cause the blood vessels to get smaller and thus result in a rise in blood pressure."
The Italian team, which Piccolo leads, reported their findings in the March 10, 2006, issue of Cell in a paper titled "Emilin1 Links TGF-beta Maturation to Blood Pressure Homeostasis." The joint first authors are Luca Zacchigna and Carmine Vecchione.
Giorgio Bressan, professor of histology at the University of Padua and senior co-author of the paper, said that the team had been studying a protein that is found in the extracellular matrix of blood vessels. That protein, called Emilin1, is closely associated with the elastic fibers of the vessels.
To gain a better understanding of the function of Emilin1, Bressan explained, in 2004, the group developed knockout mice that lacked either one or both functional copies of the gene encoding Emilin1. "These mice look normal," he said, "but when we looked closer we found that they were hypertensive."
The mice replicated some of the changes found in human hypertension: Their small arteries and arterioles were narrower in diameter than normal. As in humans, that change led to increased blood pressure, in the presence of normal blood volume and normal cardiac output.
The search was then on to explain why that was so. Piccolo noticed that Emilin1 had a cysteine-rich domain. That type of structure forms a kind of knot that is capable of grabbing hold of growth factors and modulating their activity. So he looked at a range of growth factors, to see if Emilin1 interacted with them.
He was in luck. He found that Emilin1 could inhibit the signaling pathway controlled by transforming growth factor-TGF-beta (TGF-beta). That growth factor is known to play an important role in the development of blood vessels. It is synthesized as a precursor called proTGF-beta. Emilin1, Piccolo found, inhibited the processing of proTGF-beta into TGF-beta.
The team went back and looked at the Emilin1 knockout mice, to see if they could find a functional link between Emilin1 and TGF-beta. First of all, they found that the mice had higher than normal levels of TGF-beta signaling. Secondly, when they bred mice that had only one allele encoding the gene for TGF-beta 1, instead of the normal two, they found that these animals did not have hypertensions.
"This strategy rescued the hypertensive phenotype," Bressan said. "It also implied a cause-and-effect relationship between Emilin1 and TGF-beta in hypertension."
TGF-beta is one of the most widely studied growth factors and is known to restrain the growth of cells. "By slowing down the proliferation of the smooth muscle cells of the blood vessels," Piccolo explained, "TGF-beta appears to bring about the vascular remodeling’ by which these vessels become progressively smaller, leading to the development of hypertension."
That finding also fits with earlier observations by other groups that people with severe hypertension might have high levels of circulating TGF-beta. "Until now, no one knew the significance of these observations," Piccolo said.
He concluded: "This finding breaks new ground. It allows us to envisage completely different kinds of treatment for hypertension in the future, targeting the excess of TGF-beta. These therapies could, perhaps, reverse the remodeling of the blood vessels."
Writing in Cell, the authors considered that their study has even wider implications. They wrote: "The discovery of Emilin1 as a regulator of TGF-b processing and activation may be relevant not only for hypertension, but also for many other pathological conditions in which TGF-beta has been suggested to play a role, such as atherosclerosis, inflammation, tissue repair, fibrosis and cancer."
The group is investigating hypertensive families to determine whether affected members have mutations in the gene encoding TGF-beta, or if they have higher levels of circulating TGF-beta.