Yabing Chen receives NIH grants to advance vascular disease research

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.

The first of Chen's two new R01 grants is a five-year, $2.2 million grant from the NIH National Institute on Aging to study novel regulation in vascular dementia, where vascular disease is a key risk factor.

We know that knocking out Runx2 helps versus cardiovascular disease. So will a knockout in Runx2 improve health in a mouse dementia model?"

Yabing Chen, Ph.D.

Vascular pathology has been linked to dementias, notably Alzheimer's disease and vascular dementia.

Chen's other R01 is a four-year, $2.86 million grant from the NIH National Heart, Lung, and Blood Institute to examine the role of protein methylation as a mechanism in the phenotypic modulation of vascular smooth muscle cells and subsequent calcification.

Chen says the two studies aim to elucidate not only the mechanism of calcification, but also additional associated pathogenic changes.

The canonic progression of atherosclerosis traditionally has had three steps -; inflammation, lipid deposits and finally calcification of the lesion. In a previous report by Chen's group and others, Runx2 was only recognized as acting at the calcification step. Her recent finding may change this paradigm, as her team discovered that Runx2 appears to be active at the first step, too. Chen's lab has found that knockout of Runx2 in smooth muscle cells reduces inflammation, while increasing Runx2 in the smooth muscle cells increases inflammatory molecules.

Chen hopes mechanistic understanding of Runx2's role in vascular aging will lead to therapies to mitigate vascular hardening. "There is no current treatment for vascular calcification," she said. "There are only treatments for the underlying diseases where vascular calcification is prevalent -; atherosclerosis, diabetes, chronic kidney disease and osteoporosis."

Chen's passion for vascular disease research is deeply personal, stemming from the loss her father, Yichang Chen, to a heart attack at the young age of 44, while she was still in college. This tragic event left an indelible mark on Chen, fueling her determination to study the mysteries of human disease. Her graduate studies in uncovering signaling pathways that promote cancer cell growth provided a strong foundation of later work in exploring the intricacies of vascular smooth muscle cell function in cardiovascular disease. This pivot in her research interests was recognized and support by the American Heart Association, which awarded her four-year career development funding in 2004.

Also in 2004, Chen decided to relocate to Birmingham with no immediate job prospects and the responsibility of caring for their two young children, while her husband secured a UAB faculty appointment following his postdoctoral work in Vermont. However, she was not without resources. Her AHA award was a beacon of hope. Jay MacDonald, M.D., the esteemed chair of the UAB Department of Pathology at that time, offered her an opportunity that would become a turning point in her career.

MacDonald welcomed Chen to collaborate on a cancer research project and provided her a position as a non-tenure-track assistant professor. Embracing the challenge, Chen carved out her unique niche, establishing her own research in vascular calcification and securing independent funding from both the AHA and the National Institutes of Health to further her vital studies on vascular disease.

Chen's research has flourished, and so has her academic career. Chen is now a full professor in the Department of Pathology, Division of Molecular and Cellular Pathology. She is also Pathology's vice chair for Faculty Development and Education and a senior research career scientist at the Birmingham Veterans Affairs Medical Center.

Fittingly, Chen also holds the Jay M. McDonald, M.D., Endowed Chair in Laboratory Medicine.