Spatial smooth muscle cell transition states in atherosclerosis

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Atherosclerotic cardiovascular disease (ASCVD) is responsible for myocardial infarction and ischemic stroke, leading to nearly 10 million deaths globally each year. ASCVD is characterized by plaque formation in arteries. Plaques can become unstable and rupture, resulting in obstructive thrombi and tissue ischemia. Plaques with thin fibrous caps and large necrotic cores are associated with high rupture risk. In atherosclerosis, vascular smooth muscle cells (SMCs) leave the artery wall and proliferate to form the protective, fibrous cap. After the fibrous cap is established, a subset of SMCs enters the plaque core, losing SMC markers in the process, and adopt identities of other cell types such as macrophages, fibroblasts, and chondrocytes. The SMC lineage is integral to plaque structure and comprises the majority of cells in advanced plaques. Therapies to modulate SMC behavior in plaques have great potential to enhance plaque stability and prevent cardiovascular events in patients; however, improved understanding of pathways controlling SMC fate and migration in plaques is needed. I propose to apply unbiased spatial transcriptomics technology using expertise at Yale in combination with established animal models allowing SMC lineage tracing to investigate key mechanisms determining SMC spatial transitions from the plaque cap into the plaque core. Preliminary data show that tumor necrosis factor-α (TNFα) signaling is critical for SMC incorporation in plaques, likely through TNF receptor 1 (TNFR1). Additionally, my data demonstrate that integrin β3, a protein important for SMC proliferation and identity, is selectively expressed in SMCs during atherosclerosis while SMC identity is maintained. I show that integrin β3 has reciprocal expression with CD47, a binding partner of integrin β3 with key roles in preventing efferocytosis and plaque resolution. The overarching goal of this proposal is to discover transcriptional pathways characteristic of SMC transitions and investigate whether manipulation of TNFα signaling and integrin β3 in SMCs may serve as novel therapeutic strategies to maintain fibrous cap SMCs. Aim 1 of this project analyzes spatial gene expression in plaques with SMC-lineage tracing and determines the role of TNFR1 and TNFα on SMC plaque entry from the fibrous cap. Aim 2 investigates the effect of integrin β3 expression on fibrous cap SMCs and the relationship of integrin β3 and CD47 in SMC dedifferentiation. I will also determine how loss of integrin β3 influences SMC phenotype by altering α and β integrin binding partners. Therefore, this project will evaluate key mechanisms of spatial SMC transitions in atherosclerotic plaques. Accomplishing the aims of the project will show new strategies to improve plaque structure, limit complications, and enhance quality of life for patients suffering from ASCVD. The fellowship also includes a training plan combining each of my sponsors’ expertise with Yale’s fertile environment for vascular science and medicine to prepare me for an excellent career as a physician-scientist in cardiovascular biology.