Yabing Chen, Ph.D., has been awarded two National Institutes of Health grants totaling more than $5 million to further her research into vascular diseases ranging from hardening of the arteries to dementia.
Vacuolar calcification, which leads to the hardening of blood vessels and increased vascular stiffness, is a hallmark of the aging process in the cardiovascular system. As early as the mid-1600s, physician Thomas Sydenham noted that “a man is as old as his arteries.” Chen expands that to include two different disease processes. “I like to say, ‘As we get older, soft tissue becomes hard and hard tissue becomes soft.’”
Chen’s research at the University of Alabama at Birmingham has helped show that one master transcription factor, Runx2, is involved not only in the aging disease of fragile bones known as osteoporosis, but also in the calcification of arteries. In normal growth, Runx2 is known as a master regulator of bone formation.
Chen’s lab in the UAB Department of Pathology was the first to create a tissue-specific animal model that defines the role of Runx2 in the smooth muscle cells, the main cells that wrap around arteries and act to regulate blood flow by tightening or relaxing the arteries. That increased level of Runx2 caused some of the smooth muscle cells to change into osteoblast-like cells, the cells that help build bones. This change, called smooth muscle cell phenotypic modulation, led to increased calcification by deposits of hydroxyapatite in the extracellular matrix around the smooth muscle cells. Hydroxyapatite is the ceramic material that gives structural strength to bones and teeth.
In contrast, when Runx2 is knocked out in smooth muscle cells, a majority of the smooth muscle cells maintain their phenotype in a mouse model of atherosclerosis, thus preventing calcification.
Chen has found that a common regulatory system that links the process of bone loss in osteoporosis and hardening of arteries in cardiovascular disease. According to her findings, it is the different responses in the microenvironments of bones and blood vessels that mediate the signaling pathway for Runx2. This dysfunctional regulatory pathway can lead to increased mineralization in vasculature that contributes to arterial hardening, while simultaneously decreasing bone mineralization that results in osteoporosis.