Abdominal aortic aneurysm (AAA), defined as a focal dilation of the abdominal aorta beyond 50% of its normal diameter, is a common and potentially life-threatening vascular disease. The molecular and cellular mechanisms underlying AAA pathogenesis remain unclear. Healthy endothelial cells (ECs) play a critical role in maintaining vascular homeostasis by regulating vascular tone and maintaining an anti-inflammatory, anti-thrombotic local environment. Increasing evidence indicates that endothelial dysfunction is an early pathologic event in AAA formation, contributing to both oxidative stress and inflammation in the degenerating arterial wall. Recent studies utilizing single-cell RNA sequencing revealed heterogeneous EC sub-populations, as determined by their transcriptional profiles, in aortic aneurysm tissue. This review summarizes recent findings, including clinical evidence of endothelial dysfunction in AAA, the impact of biomechanical stress on EC in AAA, the role of endothelial nitric oxide synthase (eNOS) uncoupling in AAA, and EC heterogeneity in AAA. These studies help to improve our understanding of AAA pathogenesis and ultimately may lead to the generation of EC-targeted therapeutics to treat or prevent this deadly disease.

Cardiovascular diseases, including peripheral arterial and venous disease, myocardial infarction, and stroke, are the number one cause of death worldwide annually. In the last 20 years, the role of necroptosis, a newly identified form of regulated necrotic cell death, in cardiovascular disease has come to light. Specifically, the damaging role of two kinase proteins pivotal in the necroptosis pathway, Receptor Interacting Protein Kinase 1 (RIPK1) and Receptor Interacting Protein Kinase 3 (RIPK3), in cardiovascular disease has become a subject of great interest and importance. In this review, we provide an overview of the current evidence supporting a pathologic role of RIPK1 and RIPK3 in cardiovascular disease. Moreover, we highlight the evidence behind the efficacy of targeted RIPK1 and RIPK3 inhibitors in the prevention and treatment of cardiovascular disease.

Receptor interacting protein kinase 3 (RIPK3)-mediated smooth muscle cell (SMC) necroptosis has been shown to contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). However, the signaling steps downstream from RIPK3 during SMC necroptosis remain unknown. In this study, the roles of mixed lineage kinase domain-like pseudokinase (MLKL) and calcium/calmodulin-dependent protein kinase II (CaMKII) in SMC necroptosis were investigated. We found that both MLKL and CaMKII were phosphorylated in SMCs in a murine CaCl₂-driven model of AAA and that Ripk3 deficiency reduced the phosphorylation of MLKL and CaMKII. In vitro, mouse aortic SMCs were treated with tumor necrosis factor α (TNFα) plus Z-VAD-FMK (zVAD) to induce necroptosis. Our data showed that both MLKL and CaMKII were phosphorylated after TNFα plus zVAD treatment in a time-dependent manner. SiRNA silencing of Mlkl-diminished cell death and administration of the CaMKII inhibitor myristoylated autocamtide-2-related inhibitory peptide (Myr-AIP) or siRNAs against Camk2d partially inhibited necroptosis. Moreover, knocking down Mlkl decreased CaMKII phosphorylation, but silencing Camk2d did not affect phosphorylation, oligomerization, or trafficking of MLKL. Together, our results indicate that both MLKL and CaMKII are involved in RIPK3-mediated SMC necroptosis, and that MLKL is likely upstream of CaMKII in this process.

Cell-cell communication coordinates cellular differentiation, tissue homeostasis, and immune responses in states of health and disease. In abdominal aortic aneurysm (AAA), a relatively common and potentially life-threatening vascular disease, intercellular communications between multiple cell types are not fully understood. In this study, we analyzed published single-cell RNA sequencing (scRNA-seq) datasets generated from the murine CaCl₂ model, perivascular elastase model, Angiotensin II model, and human AAA using bioinformatic approaches. We inferred the intercellular communication network in each experimental AAA model and human AAA and predicted commonly altered signaling pathways, paying particular attention to thrombospondin (THBS) signaling between different cell populations. Together, our analysis inferred intercellular signaling in AAA based on single-cell transcriptomics. This work provides important insight into cell-cell communications in AAA and has laid the groundwork for future experimental investigations that can elucidate the cell signaling pathways driving AAA.