Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

Abstract

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. Methods and 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.

Molecular Mechanisms of Pulmonary Arterial Remodeling

“…In the MCT model, however, VEGF levels appear to be decreased (78). In fact, it was reported that VEGF attenuated PAH through viral-and cell-based transfer studies in the MCT and hypoxiainduced PAH models, possibly by protecting endothelial cells from injury and apoptosis (79)(80).…”

Pathology of Pulmonary Hypertension

“…Moreover, the role of endothelial cell apoptosis in the pathogenesis of PH was also extended to the monocrotaline model [30]. Initial endothelial cell apoptosis might favor the emergence of apoptosis-resistant endothelial cells, with potential for uncontrolled proliferation [29;31].…”

The efficacy of MSC-HGF in treating pulmonary arterial hypertension (PAH) and connexin remodelling

“…Some studies have shown that gene transfer of endothelial nitric oxide synthase (eNOS) or a variety of angiogenic factors such as vascular endothelial growth factor or angiopoietin-1 can prevent endothelial cell apoptosis and induce angiogenesis of MCTinduced pulmonary hypertension in rats [25,26]. HGF has been shown to exert mitogenic, morphogenic and antiapoptotic activities in various cell types [6].…”