Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension

Background-Pulmonary arterial hypertension is characterized by increased pu lmonary vascular resistance secondary to a decrease in the caliber and numb er of pulmonary vascular channels. We hypothesized that the targeted overex pression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by prev enting the loss of existing vessels or by inducing the development of new b lood vessels within the lung. Methods and Results-We used a cell-based method of gene transfer to the pul monary microvasculature by delivering syngeneic smooth muscle cells overexp ressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 ra ts in which pulmonary hypertension was induced with the pulmonary endotheli al toxin monocrotaline. Four weeks after simultaneous endothelial injury an d cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated anima ls. Four weeks after gene transfer, the plasmid VEGF transcript was still d etectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent tran sgene expression. In addition, delay of cell-based gene transfer until afte r 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 pulmonar y hypertension in the monocrotaline model and suggest a potential therapeut ic role for angiogenic factors in the therapy of this devastating disease.