Abstract
PurposeEndothelial dysfunction is central to the pathogenesis of acute coronary syndrome. The study of diseased endothelium is very challenging due to inherent difficulties in isolating endothelial cells from the coronary vascular bed. We sought to isolate and characterise coronary endothelial cells from patients undergoing thrombectomy for myocardial infarction to develop a patient-specific in vitro model of endothelial dysfunction.MethodsIn a prospective cohort study, 49 patients underwent percutaneous coronary intervention with thrombus aspiration. Specimens were cultured, and coronary endothelial outgrowth (CEO) cells were isolated. CEO cells, endothelial cells isolated from peripheral blood, explanted coronary arteries, and umbilical veins were phenotyped and assessed functionally in vitro and in vivo.ResultsCEO cells were obtained from 27/37 (73%) atherothrombotic specimens and gave rise to cells with cobblestone morphology expressing CD146 (94 ± 6%), CD31 (87 ± 14%), and von Willebrand factor (100 ± 1%). Proliferation of CEO cells was impaired compared to both coronary artery and umbilical vein endothelial cells (population doubling time, 2.5 ± 1.0 versus 1.6 ± 0.3 and 1.2 ± 0.3 days, respectively). Cell migration was also reduced compared to umbilical vein endothelial cells (29 ± 20% versus 85±19%). Importantly, unlike control endothelial cells, dysfunctional CEO cells did not incorporate into new vessels or promote angiogenesis in vivo.ConclusionsCEO cells can be reliably isolated and cultured from thrombectomy specimens in patients with acute coronary syndrome. Compared to controls, patient-derived coronary endothelial cells had impaired capacity to proliferate, migrate, and contribute to angiogenesis. CEO cells could be used to identify novel therapeutic targets to enhance endothelial function and prevent acute coronary syndromes.
Highlights
Atherothrombosis is characterised by atherosclerotic plaque rupture with thrombus formation and is the major cause of acute coronary syndromes and cardiovascular death
Coronary atherothrombotic specimens (n = 49) are collected from consecutive patients with acute myocardial infarction with specimens fixed for histology (n = 8), flow cytometry (n = 4), or manually disaggregated for cell culture (n = 37) (Online Fig. 1)
Our results indicate that atherothrombotic specimens are a viable and important sources of endothelial cells to understand the role and the insights of endothelial dysfunction in the pathogenesis of coronary artery disease
Summary
Atherothrombosis is characterised by atherosclerotic plaque rupture with thrombus formation and is the major cause of acute coronary syndromes and cardiovascular death. Disruption of the endothelial cell monolayer has been implicated in the onset [1], progression [2], and clinical manifestations [3] of atherothrombosis This monolayer acts as a nonadhesive surface for platelets and leucocytes and produces important factors in the regulation of inflammation, thrombosis, and blood flow [4]. Whilst the number of circulating endothelial cells can be quantified in blood [9, 10] and novel methods have been developed to isolate endothelial cells from superficial veins and arteries [11], our understanding of the cellular mechanisms of endothelial dysfunction in acute coronary syndrome is largely inferred from the study of endothelial cells from more readily available vascular beds. The study of late endothelial outgrowth cells (EOCs) from peripheral blood [12, 13] whose origin is controversial [14], or commercially acquired coronary artery endothelial cells from vascular beds of unknown health, or umbilical vein endothelial cells [15] from vessels that do not develop atherosclerosis, provides important but limited insights into the pathogenesis of coronary artery disease [16, 17]
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