Introduction: Pulmonary arterial hypertension (PAH) is triggered by endothelial cell (EC) apoptosis leading directly to loss of microvasculature and indirectly to occlusive arterial remodeling, together resulting in a profound loss of functional microcirculation. We hypothesized that the hemodynamic abnormalities of PAH, in particular increased luminal shear stress, play a vital role in perpetuating EC injury and ongoing EC apoptosis, overwhelming endogenous mechanisms of microvascular repair.
Methods and Results: Severe PAH was induced by the VEGF inhibitor, SU5416 (SU, 20mg/kg), together with a 3-week exposure to hypoxia (10% O2, SUHx model) in SD rats. The left pulmonary vascular bed was protected from the effects of elevated arterial pressures and endothelial shear stress by left pulmonary arterial banding (LPAB >70% stenosis), either at 1-week prior to induction of PAH (prevention) or 5-weeks after SU (reversal). Using micro-CT, we demonstrated >80% loss in functional microcirculation by 4 weeks post SU, preceding evidence of occlusive arterial remodeling, and this was associated with persistent EC apoptosis up to 7 weeks. Ongoing EC apoptosis and complex arterial remodeling at 7-weeks were abrogated by LPAB in the prevention model, with complete preservation of the lung microcirculation. Similarly, LPAB at 5 weeks resulted in resolution of EC apoptosis and arterial remodeling, which was associated with progressive recovery of the microcirculation at 8 and 10 weeks. Moreover, removal of the band at 10 weeks resulted in a 26 mmHg decrease in right ventricular systolic pressure 3-weeks later (81±10 vs. 107±10 mmHg; p<0.05).
Conclusions: Two distinct mechanism are required for the development and progression of severe PAH in the SUHx model: the initial EC injury by SU and ongoing EC injury and apoptosis dependent on increased endothelial shear forces; the interruption of which by LPAB reveals a remarkable ability for lung microvascular repair and leads to reversal of established PAH.