By Dirk Hoffman

Yongho Bae, PhD, assistant professor of pathology and anatomical sciences, is principal investigator on the one-year, $639,543 study titled “Biomimetic Vascular Matrix for Vascular Smooth Muscle Cell Mechanobiology and Pathology.”

His research group focuses on the rapidly growing field of cellular mechanotransduction, specifically, the role that mechanical forces play in regulating cellular function.

“We are mainly interested in understanding the effects and molecular mechanisms by which changes in arterial stiffness modulate VSMC biology and mechanics in many types of pathologies, such as in vascular and cardiovascular diseases,” he says.

Arterial stiffness is a key risk factor for cardiovascular disease events, according to Bae.

“Stiffening of the vessel wall promotes abnormal migration and proliferation of VSMCs, causing neointima formation of the vessel wall,” he says. “Yet, the molecular mechanisms by which pathological extracellular matrix (ECM) stiffness regulates VSMC growth and migration associated with pathological neointima formation are unclear.”

The new study draws upon newly collected preliminary data that show a novel role for the protein survivin as a key regulator of stiffness-mediated VSMC growth and migration and an effector of arterial stiffening and remodeling.

The researchers identified the stiffness-sensitive induction of survivin as a key mechanism for stimulating VSMC proliferation and migration, and found that survivin inhibition decreases the induction of major ECM proteins directly responsible for arterial stiffness.

Using VSMCs, the study will first explore how vascular ECM stiffness impacts VSMC migration and growth at the single-cell level; and, secondly, determine how pathological ECM stiffness drives neointima formation altering the local mechanical environment of VSMCs in vitro.

“This new grant will test survivin’s role in regulating both ECM production and arterial stiffness using an in vivo animal model,” Bae says. “These aims will be achieved using a 3D cell culture using a novel in vitro porcine decellularized aorta ECM based fibrous scaffold system and engineered mouse injury models.”

The new grant will enable, for the first time, the study of molecular and biophysical mechanisms by which survivin:

• mediates stiffness-sensitive VSMC functions, and
  
• contributes to neointima formation and stiffening
  

“The aim is to reveal a completely new aspect of survivin biology in VSMCs and in the pathology of arterial stiffness,” Bae says. “Overall, this proposal is unique in its ability to identify potential new therapeutic targets for the treatment of cardiovascular disease.”

Bae says work on the grant will bring together investigators with unique expertise to elucidate how a pathological ECM environment impacts VSMC mechanobiology and contributes to arterial stiffening by using a physiologic 3D in vitro system and an in vivo model system for the overall goal of identifying new targets and therapies for the treatment of cardiovascular disease.

The team members, their roles and their areas of expertise are:

• Bae (PI) mechanobiology, vascular cell biology and atomic force microscopy
  
• Su Chin Heo, PhD, (MPI) Perelman School of Medicine, University of Pennsylvania, single-cell analysis/tissue engineering
• Robert L. Mauck, PhD, (co-I) Perelman School of Medicine, University of Pennsylvania, soft tissue mechanics
• Kwonmoo Lee, PhD, (co-I) Boston Children’s Hospital, machine learning
• John M. Canty Jr., MD, (consultant) SUNY Distinguished and Albert and Elizabeth Rekate Professor of Medicine, Jacobs School of Medicine and Biomedical Sciences, cardiovascular medicine
  
• Jason A. Burdick, PhD, (consultant) University of Colorado Boulder, biomaterials
• Wade J. Sigurdson, PhD, (consultant) director of Confocal Microscope and Flow Cytometry Facility, Jacobs School of Medicine and Biomedical Sciences, microscopy/imaging