BRITE Relaunch: Examining the Role of Mechanotransduction in Smooth Muscle Cell Phenotype Modulation

点击翻译按钮获取中文摘要

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).The vascular smooth muscle cells (VSMCs) that make up one of the layers of arteries exhibit two distinct types: contractile and synthetic. Contractile VSMCs regulate blood pressure in the artery by contracting or relaxing. However, they can revert into the synthetic type in response to an injury to the blood vessel. Synthetic VSMCs are responsible for synthesis of replacement cells and secretion of substances that are needed for vessel healing. This Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Relaunch project has hypothesizes that a third type of VSMCs exists, and the change in the cells to this third type is caused by stretch within the vascular tissue. It is further hypothesized that this change to the third type of VSMC happens through a signaling pathway known as Wnt. Through this pathway, the VSMCs become bone-like cells and deposit mineral (calcium) into the arterial tissue that surrounds the cells, the extracellular matrix. The mechanical changes leading to this potential third phenotype are caused by hypertension, known as the silent killer. By understanding the signaling pathway associated with this change in the behavior of VSMCs, future research can be supported to develop targeted therapeutics to treat vascular calcification (i.e., hardening of the arteries) at the cellular and molecular level. This work could drive future research that will reduce the severity of heart disease complications experienced by patients and reduce the costs of treating high-risk patients. This project will also increase the participation of students from underrepresented groups in research -- in particular, first-generation, low-income students. This project will advance knowledge by investigating the hypothesis that the continued plasticity of VSMCs to a third phenotype is caused by mechanical strain activating the canonical Wnt signaling pathway. An in vitro vascular calcification model will be used to examine the role of mechanotransduction in VSMC phenotype changes. This project will: 1) investigate the activation of a Wnt signaling pathway in synthetic VSMCs; 2) examine the impact of surface mechanics on the activation of phenotypic modulation via the Wnt signaling pathway; and 3) examine the phenotypic modulation of VSMCs under mechanical strain. This mechanical loading will mimic the physiological exposure of VSMCs to increased stretch due to hypertension, which is then hypothesized to cause a response within the tissue to increase its stiffness through calcification and return the range of strains to a tissue-specific homeostatic level. This mechanical transduction response is known to occur in most biological tissues, including in bone.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.