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The role of microtubule–associated protein EB3 in Pathogenesis of Pulmonary Hypertension.

Hypoxia is one of the most powerful triggers of Pulmonary Hypertension (PH) that acts directly on endothelial cells (ECs). Translocation of hypoxia inducible factors (HIFs) from the cytoplasm into the nucleus of ECs plays a critical role in the pathogenesis of PH by inducing transcription of genes containing hypoxia response elements (HREs) such as endothelin1 (ET1), which in turn, promotes vasoconstriction of smooth muscle cells. The role of microtubule (MT) cytoskeleton in the pathogenesis of pulmonary hypertension is not yet understood. Some studies suggest that MT dynamics play a critical role in nuclear translocation of HIFs, and therefore HIF function, but the results of these studies are controversial. Here, we investigated the role of end binding protein (EB3) in endothelial cells in the pathogenesis of PH through stabilization and/or nuclear translocation of HIFs in pulmonary arterial endothelial cells. In order to understand the specific role of EB3 in ECs, we developed tamoxifen‐inducible cell specific knock out (i‐KO) mouse models, allowing deletion of Mapre3 (EB3) gene in either endothelial or smooth muscle cells (SMCs). Exposure of EB3fl/fl (control) or iSMS‐KO mice to 10% hypoxia for four weeks resulted in a significant increase in right systolic ventricular pressure (RSVP) from 22±0.8 mmHg (normoxia) to ~35±0.8 and ~33±1 mmHg, respectively. This increase in RSVP was significantly mitigated in EB3 iEC‐KO mice as compared to the other two groups (p<0.0008). The protective effects of EB3 KO in ECs were even more evident when wall thickness of small arteries was compared between groups (p<0.0001). EB3 KO mice also showed decreased HIF2α immunofluorescence in nuclei of endothelial cells in lungs indicating the critical role of EB3 in HIF2α nuclear transport. Furthermore, our experiments in human pulmonary aorta endothelial cells expressing HIF2α mutants, which are not sensitive to proteolytic degradation in normoxia, conformed the role of EB3 in HIF2α trafficking. We conclude that MT cytoskeleton and EB3 are potential targets to limit HIF function in pathogenesis of PH.