Mette K Hagensen1, Jeong Shim, Troels Thim, Erling Falk, Jacob F Bentzon. 1. MSc, Atherosclerosis Research Unit, Institute of Clinical Medicine and Department of Cardiology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark. mette.hagensen@ki.au.dk
Abstract
BACKGROUND: It has been reported that circulating endothelial progenitor cells (EPCs) home to and differentiate into endothelial cells after various kinds of arterial injury. By inference, EPCs are also proposed to be important in the most important arterial disease, atherosclerosis, but the evidence for this theory is not clear. In the present study, we assessed the contribution of circulating EPCs to plaque endothelium in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: To investigate whether EPCs in the circulating blood are a source of plaque endothelial cells during atherogenesis, we examined plaques in lethally irradiated apoE(-/-) mice reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE(-/-) mice and plaques induced in segments of common carotid artery transplanted from apoE(-/-) mice into eGFP(+)apoE(-/-) mice. Among 4232 endothelial cells identified by a cell-type-specific marker (von Willebrand factor) and analyzed by high-resolution microscopy, we found only 1 eGFP(+). Using the Y chromosome to track cells after sex-mismatched transplants yielded similar results. To investigate whether circulating EPCs are involved in plaque reendothelialization after plaque disruption and superimposed thrombosis, we produced mechanical plaque disruptions in carotid bifurcation plaques in old lethally irradiated apoE(-/-) mice reconstituted with eGFP(+)apoE(-/-) bone marrow cells and carotid bifurcation plaques transplanted from old apoE(-/-) mice into eGFP(+)apoE(-/-) mice. Only 1 eGFP(+) endothelial cell was found among 3170 analyzed. CONCLUSIONS: Circulating EPCs rarely, if ever, contribute to plaque endothelium in apoE(-/-) mice. These findings bring into question the prevailing theory that circulating EPCs play an important role in atherogenesis.
BACKGROUND: It has been reported that circulating endothelial progenitor cells (EPCs) home to and differentiate into endothelial cells after various kinds of arterial injury. By inference, EPCs are also proposed to be important in the most important arterial disease, atherosclerosis, but the evidence for this theory is not clear. In the present study, we assessed the contribution of circulating EPCs to plaque endothelium in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: To investigate whether EPCs in the circulating blood are a source of plaque endothelial cells during atherogenesis, we examined plaques in lethally irradiated apoE(-/-) mice reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE(-/-) mice and plaques induced in segments of common carotid artery transplanted from apoE(-/-) mice into eGFP(+)apoE(-/-) mice. Among 4232 endothelial cells identified by a cell-type-specific marker (von Willebrand factor) and analyzed by high-resolution microscopy, we found only 1 eGFP(+). Using the Y chromosome to track cells after sex-mismatched transplants yielded similar results. To investigate whether circulating EPCs are involved in plaque reendothelialization after plaque disruption and superimposed thrombosis, we produced mechanical plaque disruptions in carotid bifurcation plaques in old lethally irradiated apoE(-/-) mice reconstituted with eGFP(+)apoE(-/-) bone marrow cells and carotid bifurcation plaques transplanted from old apoE(-/-) mice into eGFP(+)apoE(-/-) mice. Only 1 eGFP(+) endothelial cell was found among 3170 analyzed. CONCLUSIONS: Circulating EPCs rarely, if ever, contribute to plaque endothelium in apoE(-/-) mice. These findings bring into question the prevailing theory that circulating EPCs play an important role in atherogenesis.
Authors: Stanley Y Shaw; Susan Cheng; L Adrienne Cupples; Martin G Larson; Elizabeth L McCabe; Julius S Ngwa; Ying A Wang; Roderick P Martin; Rachael J Klein; Basma Hashmi; Olujimi A Ajijola; Evan Lau; Christopher J O'Donnell; Ramachandran S Vasan; Kenneth S Cohen; Thomas J Wang Journal: Circ Cardiovasc Genet Date: 2011-04-14