Abstract

Rationale: Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic for pulmonary arterial hypertension (PAH). While a phenotypic switch in pulmonary endothelial cells (EC) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. Methods: Bioinfomatics approach, patient samples and in vitro experiments were utilized. Results: By combining a meta-analysis of human iPAH-associated gene-expression microarrays and a unique gene expression profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss-of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from iPAH patients and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control as excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified BRCA1 as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. Conclusions: We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

View details for DOI 10.1165/rcmb.2013-0349OC

View details for PubMedID 24433082