Chronic Thromboembolic Pulmonary Hypertension as an Inflammation-Angiogenesis Disorder: From Thrombus Persistence to...

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious but potentially treatable complication of acute pulmonary embolism. CTEPH is characterized by persistent obstruction of the pulmonary arteries and elevated pulmonary pressure. Although organized blood clots have long been considered the primary cause, recent research indicates that CTEPH is more complex. Indeed, CTEPH encompasses ongoing endothelial dysfunction and dysregulated angiogenic recanalization within organized thrombi. Unlike previous reviews that address these pathways in isolation, this review integrates inflammation and angiogenesis into a unified mechanistic framework, incorporating recent single-cell transcriptomic data and epigenetic findings to outline the development and progression of CTEPH. The review also examines both established and emerging pathomechanisms of CTEPH, focusing on how local blood flow and endothelial activation shape the disease. Moreover, this review highlights the concept of dual vasculopathy, encompassing both significant vessel occlusions and small-vessel changes, similar to those observed in pulmonary arterial hypertension. Additionally, the review examines the role of inflammation in CTEPH, including the involvement of neutrophils, neutrophil extracellular traps, high-mobility group box 1 protein, monocytes, macrophages, and adaptive immune responses, as revealed by single-cell analyses. This review further discusses how endothelial dysfunction is linked to inflammation, thrombosis, and remodeling of the pulmonary vasculature. Particular attention is provided to abnormal von Willebrand factor levels, NF-κB signaling, and changes in gene regulation. Impaired angiogenesis appears to be a central mechanism underlying impaired thrombus resolution and the persistence of pulmonary hypertension, as shown in both human and animal studies. Collectively, these findings support the view that CTEPH is fundamentally an inflammatory and angiogenic disorder and suggest novel therapeutic targets that may complement surgery and other interventions.