Gene Therapy for Endothelial Progenitor Cell Dysfunction

Endothelial progenitor cells (EPCs) have reduced neovascularization capacity in the context of coronary artery disease (CAD) or cardiac risk factors (RFs). Since, endothelial NO synthase (eNOS) is critical to normal EPC function, we hypothesized that bone marrow cells (BMCs) from rats with RFs and E...

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Main Author: Ward, Michael Robert
Other Authors: Stewart, Duncan John
Language:en_ca
Published: 2009
Subjects:
Online Access:http://hdl.handle.net/1807/19108
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spelling ndltd-TORONTO-oai-tspace.library.utoronto.ca-1807-191082013-04-19T19:53:17ZGene Therapy for Endothelial Progenitor Cell DysfunctionWard, Michael Robertcardiovascular diseasecell therapynitric oxide0564Endothelial progenitor cells (EPCs) have reduced neovascularization capacity in the context of coronary artery disease (CAD) or cardiac risk factors (RFs). Since, endothelial NO synthase (eNOS) is critical to normal EPC function, we hypothesized that bone marrow cells (BMCs) from rats with RFs and EPCs from humans with CAD and/or RFs show dramatically reduced neovascularization capacity in vitro and in vivo, which can be reversed by eNOS overexpression. BMCs were isolated from rat models of type II diabetes and the metabolic syndrome, and we showed a significant reduction in their ability to stimulate neovascularization in vitro and in vivo. In humans, we isolated circulating ‘early EPCs’ from healthy subjects and patients with CAD and RFs, and transduced them using lentiviral vectors containing either eNOS or GFP (sham). EPCs from patients had reduced in vitro migration in response to SDF-1 or VEGF, which was reversed by eNOS-transduction. In co-culture with human umbilical vein endothelial cells (HUVECs) on Matrigel, eNOS-transduced EPCs contributed to increased and more complex angiogenic tube formation compared to sham-transduced cells. Human EPCs from patients were ineffective in enhancing ischemic hind limb neovascularization and perfusion in a nude mouse, whereas eNOS-transduced EPCs resulted in a significant improvement compared to sham-transduced cells. In a swine model of acute myocardial infarction (MI), eNOS- and non-transfected BMCs both increased left ventricular function compared to sham. However, there was no benefit to eNOS overexpression in this model. Various differences in the models and procedures may explain the incongruous results obtained. Taken together, these results show that eNOS overexpression significantly improves the neovascularization capacity of EPCs of human subjects with CAD and RFs and could represent an effective adjunctive approach for the improvement of autologous cell therapies for cardiovascular disease.Stewart, Duncan John2009-112010-02-23T20:12:11ZNO_RESTRICTION2010-02-23T20:12:11Z2010-02-23T20:12:11ZThesishttp://hdl.handle.net/1807/19108en_ca
collection NDLTD
language en_ca
sources NDLTD
topic cardiovascular disease
cell therapy
nitric oxide
0564
spellingShingle cardiovascular disease
cell therapy
nitric oxide
0564
Ward, Michael Robert
Gene Therapy for Endothelial Progenitor Cell Dysfunction
description Endothelial progenitor cells (EPCs) have reduced neovascularization capacity in the context of coronary artery disease (CAD) or cardiac risk factors (RFs). Since, endothelial NO synthase (eNOS) is critical to normal EPC function, we hypothesized that bone marrow cells (BMCs) from rats with RFs and EPCs from humans with CAD and/or RFs show dramatically reduced neovascularization capacity in vitro and in vivo, which can be reversed by eNOS overexpression. BMCs were isolated from rat models of type II diabetes and the metabolic syndrome, and we showed a significant reduction in their ability to stimulate neovascularization in vitro and in vivo. In humans, we isolated circulating ‘early EPCs’ from healthy subjects and patients with CAD and RFs, and transduced them using lentiviral vectors containing either eNOS or GFP (sham). EPCs from patients had reduced in vitro migration in response to SDF-1 or VEGF, which was reversed by eNOS-transduction. In co-culture with human umbilical vein endothelial cells (HUVECs) on Matrigel, eNOS-transduced EPCs contributed to increased and more complex angiogenic tube formation compared to sham-transduced cells. Human EPCs from patients were ineffective in enhancing ischemic hind limb neovascularization and perfusion in a nude mouse, whereas eNOS-transduced EPCs resulted in a significant improvement compared to sham-transduced cells. In a swine model of acute myocardial infarction (MI), eNOS- and non-transfected BMCs both increased left ventricular function compared to sham. However, there was no benefit to eNOS overexpression in this model. Various differences in the models and procedures may explain the incongruous results obtained. Taken together, these results show that eNOS overexpression significantly improves the neovascularization capacity of EPCs of human subjects with CAD and RFs and could represent an effective adjunctive approach for the improvement of autologous cell therapies for cardiovascular disease.
author2 Stewart, Duncan John
author_facet Stewart, Duncan John
Ward, Michael Robert
author Ward, Michael Robert
author_sort Ward, Michael Robert
title Gene Therapy for Endothelial Progenitor Cell Dysfunction
title_short Gene Therapy for Endothelial Progenitor Cell Dysfunction
title_full Gene Therapy for Endothelial Progenitor Cell Dysfunction
title_fullStr Gene Therapy for Endothelial Progenitor Cell Dysfunction
title_full_unstemmed Gene Therapy for Endothelial Progenitor Cell Dysfunction
title_sort gene therapy for endothelial progenitor cell dysfunction
publishDate 2009
url http://hdl.handle.net/1807/19108
work_keys_str_mv AT wardmichaelrobert genetherapyforendothelialprogenitorcelldysfunction
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