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COLUMBIA, Mo. – Human arteries – some smaller than a strand of hair – stiffen as a person ages. This stiffening is a factor in cardiovascular disease, the leading cause of death in the United States, because it contributes to the circulatory complications in disorders such as high blood pressure and diabetes. University of Missouri researchers have now used advanced 3-D microscopic imaging technology to identify and monitor the proteins involved in this stiffening process. These findings could eventually help researchers and physicians understand and treat complications associated with cardiovascular disease.

“A majority of the scientific knowledge of how blood vessels are put together is based on older methodologies that only measured the amount of protein in the artery wall and not how the proteins were architecturally arranged to support artery functions,” said Gerald Meininger, director of the MU Dalton Cardiovascular Research Center and Margaret Proctor Mulligan Professor of Medical Pharmacology and Physiology. “We used state-of-the-art imaging technology and computer-based models to visualize the minute structural elements within an intact blood vessel and found that one of the proteins, elastin, plays a key role in supporting the ability of the arterial wall to properly function.”

As people age, the level of elastin diminishes and other proteins, such as collagen, contribute to altering the arterial stiffness. The researchers believe that learning how to alter elastin levels may alleviate some of the detrimental results associated with vascular aging, such as high blood pressure.

“When people think of blood vessels, they tend to think of rigid pipes, but blood vessels are very dynamic because they continually expand and contract to adjust blood flow and blood pressure to meet the body’s needs,” said Michael Hill, also of the Dalton Cardiovascular Research Center and Professor of Medical Pharmacology and Physiology. “Elastin production peaks at a very young age and declines throughout life.  Molecular biologists are trying to determine how to turn elastin production back on in the correct places, but it has proven very difficult so far.”

The MU researchers believe the knowledge also may be used in future efforts to develop artificial vascular structures to improve tissue replacement. Blood vessels sometimes fail during the tissue replacement process, and understanding how vessels are built and change could lead to a better success rate.

The study, “Spatial Distribution and Mechanical Function of Elastin in Resistance Arteries,” was published in Arteriosclerosis, Thrombosis, and Vascular Biology, the Journal of the American Heart Association. The study was funded by the National Institutes of Health.

Researchers at The University of Western Ontario have discovered a strategy for stimulating the formation of highly functional new blood vessels in tissues that are starved of oxygen. Dr. Geoffrey Pickering and Matthew Frontini at the Schulich School of Medicine & Dentistry developed a strategy in which a biological factor, called fibroblast growth factor 9 (FGF9), is delivered at the same time that the body is making its own effort at forming new blood vessels in vulnerable or damaged tissue. The result is that an otherwise unsuccessful attempt at regenerating a blood supply becomes a successful one. Their findings are published online in Nature Biotechnology.

“Heart attacks and strokes are leading causes of death and disability among Canadians. Coronary bypass surgery and stenting are important treatments but are not suitable for many individuals,” explains Dr. Pickering, a professor of Medicine (Cardiology), Biochemistry, and Medical Biophysics, and a scientist at the Robarts Research Institute. “Because of this, there has been considerable interest in recent years in developing biological strategies that promote the regeneration of a patient’s own blood vessels.”

This potential treatment has been termed ‘therapeutic angiogenesis’. “Unfortunately and despite considerable investigation, therapeutic angiogenesis has not as yet been found to be beneficial to patients with coronary artery disease. It appears that new blood vessels that form using approaches to date do not last long, and may not have the ability to control the flow of blood into the areas starved of oxygen.”

The work of Dr. Pickering and collaborators provides a method to overcome these limitations. This strategy is based on paying more attention to the “supporting” cells of the vessel wall, rather than the endothelial or lining cells of the artery wall. The research team found that by activating the supporting cells, new blood vessel sprouts in adult mice did not shrivel up and disappear but instead lasted for over a year. Furthermore, these regenerating blood vessels were now enveloped by smooth muscle cells that gave them the ability to constrict and relax, a critical process that ensures the right amount of blood and oxygen gets to the tissues.

“FGF9 seemed to ‘awaken’ the supporting cells and stimulated their wrapping around the otherwise fragile blood vessel wall” said Frontini, the first author of the manuscript. “The idea of promoting the supporting cellular actors rather than the leading actors opens new ways of thinking about vascular regeneration and new possibilities for treating patients with vascular disease.”

Angiogenesis, the development of new blood vessels, is required during embryonic development and wound healing, as well as during disease processes such as tumor growth. The signals that direct angiogensis are incompletely understood, but could represent novel targets for the development of therapies that promote or inhibit this process.

In this paper, Young-Guen Kwon and colleagues, of Yonsei University in Seoul, Korea, investigated the role of two related proteins- DKK1 and DKK2- in angiogenesis. These proteins are known to have similar functions in inhibiting a particular cell signaling pathway, but Kwon and colleagues found that they played opposite roles in directing angiogenesis. Remarkably, they discovered that injection of DKK2 improved vascular regeneration in a mouse model of myocardial infarction (heart attack). The researchers are hopeful that pharmacological manipulation of DKK1 and DKK2 could be used to treat various vascular diseases.