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1 Pathobiology, Cleveland Clinic, Cleveland, Ohio, United States; Cleveland State University, Cleveland, Ohio, United States
2 Pathobiology, Cleveland Clinic, Cleveland, Ohio, United States
3 pathobiology, Cleveland clinic, cleveland, Ohio, United States
4 Imaging Facility, Cleveland Clinic, Cleveland, Ohio, United States
5 Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
6 Pathobiology, Cleveland Clinic, Cleveland, Ohio, United States; Pulmonary, Allergy & Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: erzurus{at}ccf.org.
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. In comparison to control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by BrdU incorporation and Ki-67 nuclear antigen expression, and decreased apoptosis as determined by caspase 3 activation and TUNEL assay. IPAH cells had greater migration than control cells, but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream pro-survival target, Mcl1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.
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