Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling

Pulmonary hypertension (PH) induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Dysfunction of endothelial cells is the hallmark event in the progression of PH. Among various mechanisms, endothelial to mesenchymal transition (EndoMT) has emerged as an important source of endothelial cell dysfunction in PH. However, the mechanisms underlying the EndoMT in PH remain largely unknown. Our results showed that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) expression was decreased in pulmonary arterial endo-thelial cells (PAECs) in PH patients and hypoxia-induced PH mouse model compared to the normal controls. Endothelial-specific overexpression of PGC-1 alpha using nanoparticle delivery significantly attenuated the progres-sion of PH, as shown by the significantly decreased right ventricular systolic pressure and diminished artery thickness as well as reduced vascular muscularization. Moreover, Endothelial-specific overexpression of PGC-1 alpha blocked the EndoMT of PAECs during PH, indicating that loss of PGC-1 alpha promotes PH development by mediating EndoMT, which damages the integrity of endothelium. Intriguingly, we found that PGC-1 alpha overexpression rescued the expression of endothelial nitric oxide synthase in mouse lung tissues that was deceased by hypoxia treatment in vivo and in endothelial cells treated with TGF-8 in vitro. Consistently, PAECs and vascular smooth muscle co-culture showed that overexpression of PGC-1 alpha in PAECs increases nitric oxide release, which would likely diffuse to smooth muscle cells, where it activates specific protein kinases, and initiates SMC relaxation by diminishing the calcium flux. Endothelial-specific overexpression of PGC-1 alpha also attenuated hypoxia-induced pulmonary artery stiffness which appeared to be caused by both the decreased endothelial nitric oxide pro-duction and increased vascular remodeling. Taken together, these results demonstrated that endothelial-specific delivery of PGC-1 alpha prevents PH development by inhibiting EndoMT of PAECs and thus restoring endothelial function and reducing vascular remodeling.

Automated summary

This study found that endothelial cell dysfunction is a key factor in pulmonary hypertension induced by chronic hypoxia and concluded that endothelial to mesenchymal transition (EndoMT) plays an important role in this process. The delivery of nanoparticle-mediated endothelial-specific overexpression of PGC-1 alpha can attenuate the progression of PH, restore endothelial function, and reduce vascular remodeling.