Human endothelial cell heterogeneity and activation in atherosclerosis

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ABSTRACT Atherosclerosis is the primary pathobiology underlying ischemic heart disease (IHD) which is the leading cause of morbidity and mortality worldwide. Atherosclerosis occurs in-part through inflammation-induced abnormalities of endothelial cells (EC), including decreased barrier function, endothelial-to-mesenchymal transition, and aberrant angiogenesis. EC state transitions in atherosclerosis are thus novel therapeutic targets, however the cell state transitions remain largely uncharacterized. Existing single cell (sc) RNA datasets of human atherosclerosis provide unprecedented opportunity to identify novel EC activation states that populate human plaques. However, the value of such annotations in vivo will only be as powerful as our ability to interpret their corresponding functional states and underlying mechanisms. Therefore, the proposed research will complement in vivo analysis of human plaques by testing the ability of putative pro-atherogenic in vitro EC models to recapitulate in vivo EC molecular signatures. Moreover, a role for the endothelial-restricted transcription factor ERG has recently been clarified in the regulation of endothelial homeostasis, cell activation, angiogenesis, and inflammation. ERG phosphorylation is required for quiescent (non-activated) physiologic angiogenesis. Yet, ERG is diminished in the most vulnerable regions of human advanced atherosclerotic lesions where angiogenesis still occurs. This indicates that inflammation-induced angiogenesis occurs independent of ERG phosphorylation though a separate mechanism downstream of IL-1b. The overarching hypothesis is that IL-1b-induced angiogenesis is a hallmark of EC pathophysiology in human atherosclerotic lesions and that this angiogenesis is mediated by NF-kb, rather than physiological ERG phosphorylation. The goal of this proposal is to move toward development of diagnostic strategies identifying vulnerable atherosclerotic lesions, and therapies that may act in synergy with existing lipid approaches to promote vascular health. The integrated research and clinical training plan will enhance the applicant’s knowledge and technical, clinical, and professional skills, and facilitate her transition to the next career stage as a productive physician-scientist dedicated to academic medicine. The interdisciplinary focus and collaborative nature of the University of Arizona provides a rich training environment to complete the proposed aims and nurture the applicant’s scientific career.