Neutrophil Extracellular Traps Promote Angiogenesis

Abstract

Objective— Inflammation and dysregulated angiogenesis are features of endothelial dysfunction in pulmonary hypertension. Neutrophil extracellular traps (NETs), produced by dying neutrophils, contribute to pathogenesis of numerous vascular disorders but their role in pulmonary hypertension has not been studied. We sought evidence of (NETs) formation in pulmonary hypertension and investigated the effect of NETs on endothelial function. Approach and Results— Plasma and lung tissues of patients with pulmonary hypertension were analyzed for NET markers. The effects of NETs on endothelial function were studied in vitro and in vivo. Patients with chronic thromboembolic pulmonary hypertension and idiopathic pulmonary hypertension showed elevated plasma levels of DNA, neutrophil elastase, and myeloperoxidase. NET-forming neutrophils and extensive areas of NETosis were found in the occlusive plexiform lesions and vascularized intrapulmonary thrombi. NETs induced nuclear factor κB–dependent endothelial angiogenesis in vitro and increased vascularization of matrigel plugs in vivo. Angiogenic responses were associated with increased release of matrix metalloproteinase-9, heparin-binding epidermal growth factor–like growth factor, latency-associated peptide of the transforming growth factor β1, and urokinase-type plasminogen activator, accompanied by increased endothelial permeability and cell motility. NETs-induced responses depended on myeloperoxidase/H 2 O 2 -dependent activation of Toll-like receptor 4/nuclear factor κB signaling. NETs stimulated the release of endothelin-1 in HPAECs (human pulmonary artery endothelial cells) and stimulated pulmonary smooth muscle cell proliferation in vitro. Conclusions— We are the first to implicate NETs in angiogenesis and provide a functional link between NETs and inflammatory angiogenesis in vitro and in vivo. We demonstrate the potential pathological relevance of this in 2 diseases of disordered vascular homeostasis, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

“…An elevated neutrophil-to-lymphocyte ratio in the peripheral blood is associated with a poor prognosis in pulmonary hypertension patients [59], speculated to be due, in part, to neutrophil extracellular trap promotion of inflammatory angiogenesis [60]. These findings are consistent with established experimental data derived from sheep and rabbit models of disease, which demonstrate that granulocyte depletion is protective against pulmonary hypertension [61,62].…”

Pathogenesis of Chronic Plaque Psoriasis and Its Intersection With Cardio-Metabolic Comorbidities

“…Consistently, aortic vascular inflammation in psoriatic patients has been found to correlate with disease severity and high levels of S100A8/A9 neutrophil activation markers (Naik et al, 2015). In addition, the neutrophil extracellular traps (NET)osis, a defense mechanism operating in psoriasis and based on the formation of cytosolic granule proteins containing autoantigens, has been found to induce macrophage priming, Th17 activation, and immune cell recruitment in atherosclerosis similarly to psoriasis (Aldabbous et al, 2016;Delgado-Rizo et al, 2017;Doring et al, 2017). NET are also shown to directly induce endothelial dysfunction and plaque rupture in human carotid plaque sections (Quillard et al, 2015).…”

Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis

“…Delayed thrombus resolution is a clinical challenge that increases the risk of DVT recurrence and of post thrombotic syndrome, two conditions associated with high morbidity and increased risk of death 39 . Also pulmonary embolism 40 and chronic thromboembolic pulmonary hypertension 41 , 42 are characterized by strong thrombo-inflammatory responses and are potentially life threatening diseases, in which the inflammatory burden correlates with adverse outcomes. In the arena of atherosclerosis, coronary heart disease and atherothrombosis, the interrelationship between inflammation and adverse outcomes has been studied in much more detail 43 .…”