Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension.
BACKGROUND
Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung.


RESULTS
We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy.


CONCLUSIONS
These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.
Campbell
A I
AI
Division of Cardiac Surgery, University of Toronto, Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Ontario, Canada.
Zhao
Y
Y
Sandhu
R
R
Stewart
D J
DJ
D000818:Animals; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D005456:Fluorescent Dyes; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008222:Lymphokines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D008833:Microcirculation / Q000187:drug effects; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014185:Transplantation, Isogeneic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005456:Fluorescent Dyes; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016686:Monocrotaline