Implantation of Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase Improves Right Ventricular Impairments Caused by Pulmonary Hypertension

Abstract

Background-Pulmonary hypertension (PH) is a life-threatening disease. Bone marrow cell transplantation is reported to reduce the development of PH by increasing vascular beds in pulmonary circulation. However, adenoviral overexpression of endothelial nitric oxide synthase (eNOS) in the lung is also known to reduce PH. Because mesenchymal stem cells (MSCs) are potential cell sources for neovascularization, the implantation of MSCs overexpressing eNOS (MSCs/eNOS) may further improve the surgical results. We evaluated the efficacy of MSCs/eNOS implantation in monocrotaline (MCT)-induced PH rats. Methods and Results-MSCs were isolated from rat bone marrow. PH was induced in rats by subcutaneous injection of MCT. One week after MCT administration, the rats received 3 different treatments: MSCs (MSC group), MSCs/eNOS (MSC/eNOS group), or nontreatment (PH group). As the negative control, rats received saline instead of MCT (control group). Right ventricular (RV) hypertrophy and the elevation of RV systolic pressure (RVSP) were evaluated 3 weeks after MCT administration. Moreover, the effects of MSCs/eNOS on survival were investigated in PH induced by MCT 3 weeks earlier. RVSP in both the MSC and MSC/eNOS groups was significantly lower than the PH group. RVSP in the MSC/eNOS group was significantly lower than the MSC group. The RV weight to body weight ratio was significantly lower in the MSC and MSC/eNOS groups than the PH group. The survival time of rats receiving MSCs/eNOS was significantly longer than the nontreatment rats. Conclusion-Intravenous

Molecular pathogenesis of pulmonary arterial hypertension

“…Mesenchymal cells have also been delivered intratracheally to attenuate monocrotaline-induced PH through an obscure mechanism. In addition, these cells have been engineered to improve myocardial performance following injection into the right ventricles in rodent PAH models (121). EPCs transfected with eNOS not only prevent but also reverse PAH in rats by reestablishing connections between proximal and distal pulmonary arteries (122).…”

Advances in Therapeutic Interventions for Patients With Pulmonary Arterial Hypertension

“…155 Mesenchymal stem cellbased gene therapies with overexpression endothelial NOS and PGI 2 synthase have both been shown to ameliorate rat models of PH. 156,157 The safety and efficacy of mesenchymal stem cell transplantation in humans have not been reported to date. An improved understanding of the homing, engraftment, and paracrine effects of stem cells in injured pulmonary vessels are needed for therapeutic application to progress.…”

Chronic pulmonary hypertension and nitric oxide

“…Ин фузия эндотелий подобных потомственных клеток костного мозга предотвращает развитие легочной гипертонии после повреждения сосудов и останав ливает прогрессирование уже возникшей легочной гипертонии [35]. Потомственные клети костного мозга, перенесенные с геном eNOS, использовались для лечения легочной гипертонии, и это приводило к нормализации систолического давления в правом желудочке, улучшению легочной микрососудистой перфузии, а также повышению выживаемости [36]. Показано, что введение указанных клеток в микро циркуляцию легких при легочной гипертонии улуч шает ремоделирование микрососудов, связанное с легочной гипертонией, как путем прямого восста новления эндотелия, так и паракринными сигна лами, стимулирующими локальные репаративные процессы.…”