Abstract

Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology but different causal mechanisms may reflect a need for patient-tailored therapies.Endothelial cells differentiated from induced pluripotent stem cells were compared to pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns, that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of BMPR2 and its target, collagen IV, pSMAD1/5 signaling and transcriptomic profiles were also analyzed.Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from idiopathic and heritable pulmonary arterial hypertension patients compared to controls, showed a similar reduction in adhesion, migration, survival, and tube formation, decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high KISS1 related to reduced migration and low CES1, to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK-506 and Elafin, was related to reduced SLIT3, an anti-migratory factor.Despite the site of disease in the lung our study indicates that induced pluripotent stem cell derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.

View details for PubMedID 27779452