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by Christina Crowe

Yabing Chen, Ph.D., the Jay M. McDonald Endowed Chair in Laboratory Medicine and Vice Chair of Faculty Development and Education, has received two R01 awards amounting to more than $5 million to bolster her research program on vascular aging and dementia.

With an overarching goal to understand vascular health in depth, Chen and her team delve into exploring the role of smooth muscle cell  phenotypic modulation and reprogramming, and their links to vascular diseases and aging. The first R01, a $2.2 million award from the National Institute on Aging, funds their research on the “Novel Regulation of Vascular Dementia”. The second R01, a $2.86 million award from the National Heart Lung and Blood Institute, funds their cardiovascular research on “Protein Arginine Methylation in Vascular Smooth Cell Phenotypic Modulation and Calcification.” Both grants will run through 2027.

Yabing Chen

Together, these grants support Chen’s ambitious goal of better understanding vascular health to potentially identify a target for diagnosis and drug discovery—research she has dedicated her career to.

“We’re trying to understand how the vascular cells function and change during the aging process,” Chen says. “Our research program investigates what controls the regulation of the vascular cell function and how this impacts the development of cardiovascular disease and vascular dementia.”

Aging accelerates pathogenesis of a variety of diseases, including cardiovascular and Alzheimer’s disease (AD), which are the leading cause of mortality and mobility in the U.S. and worldwide. Chen uses the aphorism that, “A man is as old as his arteries,” to underscore the significance of vascular health in aging. Vascular aging, characterized by age-related molecular, structural and functional changes in blood vessels, not only impairs normal vascular contraction and compliance but also increases the risk of cardiovascular disease, exacerbates vascular complications in metabolic diseases such as diabetes, and accelerates cognitive impairments and dementia, she says.

In the first awarded project, Chen and her team will test the novel concept of the pan-vascular regulation on the development of cognitive impairment and dementia. Vascular pathologies across all vascular beds have been linked to dementia, particularly the two major subtypes, AD and vascular dementia (VaD). VaD is the second most common cause of dementia that often leads to progressive cognitive impairment similar to AD. Notably, pan-vascular diseases such as atherosclerosis, stroke and hypertension accelerate the progression of cognitive impairments and dementia of all causes.

Multiple large genome-wide studies have identified common genetic risk factor for both atherosclerosis and AD, such as apolipoprotein E. However, the clinical management and mechanistic studies for atherosclerosis and AD are often conducted separately; and current treatment strategies focusing on local lesions for AD and dementia have not yielded satisfactory outcomes. This research project, which aims to address pan-vascular pathogenesis on cognitive function in VaD and AD, may open up new avenues for understanding these conditions, Chen says.

The mechanistic studies will focus on understanding the molecular processes governing vascular calcification, which is characterized by abnormal calcium deposition in blood vessels, and is a common pathological feature in atherosclerosis and aging.  Emerging research over the past two decades has greatly enhanced our understanding of vascular calcification, which is now recognized as an active cell-driven process characterized by the osteogenic differentiation of vascular cells. Vascular smooth muscle cells  play a major role in atherosclerotic intimal calcification and medial calcification independent of atherosclerosis. By generating a novel animal model, Chen and colleagues have provided the first genetic evidence of the essential role of the Runt-related transcriptional factor 2 (Runx2), the master osteogenic transcription factor, in regulating vascular calcification. Runx2 expression is very low in normal vessels but it is elevated in calcified vascular tissues.  The intriguing preliminary discovery of Runx2 upregulation during vascular aging and in Alzheimer’s disease has prompted further research to uncover Runx2-dependent regulatory mechanisms in vascular aging, atherosclerosis, and AD. The goal is to provide new insights into the precision management of vascular aging, VaD, and AD.   

Over the last decade, research from Chen’s group and others has revealed signaling cascades that increase the expression of Runx2, driving osteogenic differentiation and calcification of smooth muscle cells under various pathological conditions, including atherosclerosis, diabetes and renal disease. Conversely, her team has shown that dietary potassium inhibits Runx2 and the development of vascular calcification in atherosclerosis. This study highlighted by the National Institutes of Health, supports the potential of dietary approaches to prevent vascular aging and improve vascular health.  Furthermore, her team has demonstrated that post-translational modifications  of Runx2, including phosphorylation, ubiquitination and O-GlcNAcylation, regulates Runx2 stability and its transcriptional activity in vascular calcification.

In the second newly awarded project, Chen and colleagues will delve deeper into the novel regulation of Runx2 by protein arginine methylation, via the protein arginine methyltransferase 1 (PRMT1). PRMT1 is an emerging regulator in human pathological processes, but its function in vascular calcification and atherosclerosis is entirely unknown. The discovery that PRMT1 acts as a new Runx2 suppressor in SMC reveals a novel regulatory paradigm highlighting the PRMT1-dependent Runx2 signaling axis in modulating SMC phenotype and reprogramming in cardiovascular diseases. 

Understanding vascular aging, independent of traditional risk factors, is crucial, as it promotes vascular pathologies across all vascular beds that accelerate pathogenesis of end organ diseases, Chen says. Her newly awarded research projects aim to elucidate the novel regulation and function of Runx2 and Runx2-dependent signaling networks in vascular aging and their impact on atherosclerosis and AD.

With the expertise and resource synergy in the multidisciplinary team, Chen’s research program will utilize cutting-edge technologies to uncover new mechanisms that are transformational..  Her team hopes to bridge existing knowledge gaps in vascular aging.  By identifying new therapeutic targets, her program holds potential for innovative clinical interventions to mitigate vascular aging and age-related diseases.

Chen’s key collaborators for this program include (at UAB): Drs. Zechen Chong, Assistant Professor, Genetics, Jeonga Kim, Associate Professor, Department of Medicine, Lin Chen, Associate Professor, Neurology, Rati Chkheidze, Assistant Professor, Pathology and Paul Benson, Ph.D., Associate Professor, Pathology, and Xinyang Zhao, Associate Professor, University of Kansas. Her work is also supported by multiple core facilities at UAB, including the Single Cell, Proteomics, and Animal Phenotype, Behavior cores