Maternal endothelial progenitor colony-forming units with macrophage characteristics are reduced in preeclampsia.

The cardiovascular adaptation to pregnancy involves a complex maternal response to the presence of the growing conceptus, including alterations in vascular endothelial cells that contribute to a profound fall in peripheral vascular resistance. There is extensive evidence that maternal endothelial cell dysfunction underlies the hypertension, proteinuria and multi-organ damage that occurs during preeclampsia. The mechanism of altered endothelial homeostasis in the pathophysiology of preeclampsia, however, remains poorly understood.1,2 Endothelial progenitor cells (EPCs) are a heterogeneous group of circulating cells derived from bone marrow as well as nonmarrow sites. These cells are thought to play a role in vascular remodeling and maintenance of the adult endothelium by releasing growth factors that contribute to paracrine support and repair of the endothelial lining, and in some cases by physically incorporating into regenerating endothelium.3–9 Since the first report of EPCs by Asahara et al.,10 both flow cytometry and cell culture-based approaches have been developed to distinguish and quantify different subpopulations of circulating EPCs.7,9,11 The culture of peripheral blood mononuclear cells under certain conditions favors the formation of discrete colonies termed endothelial colony-forming units (CFU-ECs or CFUs) that are characterized by a central core of rounded cells with multiple spindle-shaped cells radiating from the central cluster.5,9,10,12 CFUs are derived from hematopoietic stem cells and exhibit monocyte/macrophage characteristics while expressing some endothelial-lineage markers. Although they remain under the classification umbrella of EPCs in the literature, the cells that comprise these CFUs do not differentiate into endothelial cells or assemble into vascular networks in vitro.6,9 Hill et al.5 observed a direct relationship between the number of CFUs and brachial artery endothelium-dependent vasodilatory function in individuals with varying degrees of cardiovascular risk but without history of cardiovascular disease. In this study, CFU numbers were a stronger predictor of flow-mediated brachial reactivity than conventional (Framingham) risk factors. The concentration of CFUs in culture is decreased in nonpregnant patients with type 1 diabetes, chronic obstructive pulmonary disease, congestive heart failure, acute stroke, rheumatoid arthritis, and in overweight and obese compared to normal weight adults.13–18 Circulating EPCs are reportedly reduced in patients with type 2 diabetes and further reduced with concomitant peripheral vascular disease.19 Reports regarding EPCs, including CFUs, in both peripheral vascular disease and essential hypertension, however, have been inconsistent.20–24 CFU-derived cells have been shown to improve blood low recovery and capillary density in animal models of hind-limb ischemia or myocardial ischemia.6,25 Data further suggest that they synergize with other EPC subpopulations to increase vascular repair and protect against endothelial disease.6,25 We tested the hypothesis that CFUs obtained from maternal peripheral blood are decreased in women with preeclampsia compared to normal pregnancy. We evaluated CFU endothelial and monocyte/macrophage characteristics in the setting of pregnancy and whether fetal cells could be detected among the cells comprising CFUs. Given the importance of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in mobilization of EPCs from bone marrrow,8 we also hypothesized that CFU counts would correlate positively with plasma concentrations of free PlGF and correlate inversely with soluble fms-like tyrosine kinase-1 (sFlt-1; also known as soluble VEGF receptor-1), an antiangiogenic factor increased in most women with preeclampsia that binds and thus neutralizes VEGF and PlGF.26