Abstract 11090: Therapeutic Effect of VEGF- and SDF-Nanoparticles in the Rat Monocrotaline Model of Pulmonary Hypertension

Abstract

Introduction: Pulmonary vascular endothelial cell injury, dysfunction, and apoptosis are associated with the development of pulmonary arterial hypertension (PAH). Improving endothelial function may be therapeutically beneficial in this disorder. In the present study, we examined the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α), proteins that support endothelial repair and tissue regeneration, in rats with monocrotaline-induced PAH. A polysaccharide nanoparticle was used as a carrier for VEGF and SDF-1α delivery, the formulation of which extends the retention time of the proteins in the lung by ~17-fold compared with free protein. Method: A crosslinked dextran sulfate-chitosan nanoparticle (XDSCS NP) was prepared as the carrier. Recombinant human VEGF and SDF-1α were incorporated in the XDSCS NP to generate VEGF-NP and SDF-NP, respectively. Athymic nude rats were injected with monocrotaline (50 mg/kg, IP) to induce PAH. Two weeks after the injection, VEGF-NP (8 μg/rat) and SDF-NP (4 μg/rat) were delivered to the lungs of rats via intratracheal aerosolization. At 4 weeks, catheterization of right and left heart was performed, and lung tissue collected for histological analysis. Results: Monocrotaline induced PAH in the nude rats, leading to right ventricular systolic pressure (RVSP) of 71±8 mmHg (mean±SD, n=8) vs. 29±2 mmHg in the untreated control rats. VEGF-NP and SDF-NP treatment reduced the RVSP to 48±13 mmHg. The Fulton indices of the three groups were 0.45±0.07, 0.22±0.01, and 0.25±0.06, respectively. The pulmonary vascular resistance indices of the groups were 3.2±0.7, 0.6±0.3, and 2.1±1.0 mmHg.min/ml/kg, respectively. Histological analysis showed monocrotaline-treated rats had prominent muscularization of precapillary vessels, which was markedly reduced by the VEGF-NP and SDF-NP treatment. Aerosolization of free VEGF and SDF-1α or of empty XDSCS NP carrier had no effect on monocrotaline-induce PAH. Conclusion: These data indicate that the delivery of VEGF and SDF to the lungs of rats in a NP-bound form had beneficial therapeutic effects in monocrotaline-induced PAH, and offer the potential for a novel therapeutic strategy for human pulmonary hypertensive disorders.