Establishment of an in vitro model to investigate extracellular matrix and vascular mechanical interactions in human arterial disease
Atherosclerosis is one of the leading causes of global death and a major threat to long and healthy lives in modern societies. Animal models of atherosclerosis have the potential to overcome many of the inherent restrictions of human research. Indeed, there have been many decades of research in mouse models that have led to >800 different ways of inhibiting atherosclerosis development. Yet, the translation of therapies designed to target molecular mechanisms of atherosclerotic plaques in mice has not made its way into routine clinical practice. This phenomenon may arise in part from the fact that atherosclerosis in mice is quite different from that in humans.
In healthy arteries, proper cell function is controlled tightly by the local microenvironment composed of a wide spectrum of proteins, signal molecules, and mechanical forces. During the development of atherosclerosis and other arterial diseases, vascular smooth muscle cells (SMC) located in the vessel wall react to the changes in their surroundings and become rapidly-dividing and disease-promoting cells. A similar shift in cell phenotype is observed when SMC are removed from their native environment and placed in culture. How do they know the difference? Classical studies describing SMC function have been performed under standard culture conditions, in which cells adhere to a hard- and static plastic plate. While these studies have contributed to the discovery of several molecular targets, they faced one limitation: the biochemical signals, such as extracellular matrix composition and mechanical cues, that control SMC function in arteries are not present. For that reason, SMC involvement in arterial diseases is today mostly studied in live animals.
In this project, we will establish a new in vitro model that more closely resembles the mechanical and physiological conditions from a native artery environment during healthy and disease conditions. Using this model, we seek to identify the specific mechanisms that regulate SMC phenotypic modulation to understand their relevance in human arterial disease. The goal is to establish techniques that can replace live animals for research in SMC function and to increase our understanding of the mechanisms that lead to the accumulation of unconventional SMC types atherosclerosis and other vascular pathologies.
- Establishment of an in vitro model to investigate extracellular matrix and vascular mechanical interactions in human arterial disease (final report, September 2021)
- Article (MDPI): The Phenotypic Responses of Vascular Smooth Muscle Cells Exposed to Mechanical Cues (September 30, 2021)
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