Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature.

Hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents. The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells. The genetic deletion of Hif-2α but not Hif-1α caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation. Our findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.

Jiang X ，Tian W ，Tu AB ，Pasupneti S ，Shuffle E ，Dahms P ，Zhang P ，Cai H ，Dinh TT ，Liu B ，Cain C ，Giaccia AJ ，Butcher EC ，Simon MC ，Semenza GL ，Nicolls MR ... -  《-》

Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus.

Jiang X ，Hsu JL ，Tian W ，Yuan K ，Olcholski M ，Perez Vde J ，Semenza GL ，Nicolls MR ... -  《-》

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection.

Jiang X ，Khan MA ，Tian W ，Beilke J ，Natarajan R ，Kosek J ，Yoder MC ，Semenza GL ，Nicolls MR ... -  《-》

Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema.

Jiang X ，Tian W ，Granucci EJ ，Tu AB ，Kim D ，Dahms P ，Pasupneti S ，Peng G ，Kim Y ，Lim AH ，Espinoza FH ，Cribb M ，Dixon JB ，Rockson SG ，Semenza GL ，Nicolls MR ... -  《-》

Unraveling the role of hypoxia-inducible factor (HIF)-1α and HIF-2α in the adaption process of human microvascular endothelial cells (HMEC-1) to hypoxia: Redundant HIF-dependent regulation of macrophage migration inhibitory factor.

Hypoxia driven angiogenesis is a prominent feature of tissue regeneration, inflammation and tumor growth and is regulated by hypoxia-inducible factor (HIF)-1 and -2. The distinct functions of HIFs in the hypoxia-induced angiogenesis and metabolic switch of endothelial cells are still unknown and therefore aim of this study. We investigated the role of HIF-1 and -2 in the adaptation of immortalized human microvascular endothelial cells (HMEC-1) to hypoxic conditions (1% O2) in terms of angiogenesis, cytokine secretion, gene expression and ATP/ADP-ratio using shRNA-mediated reduction of the oxygen sensitive α-subunits of either HIF-1 or HIF-2 or the combination of both. Reduction of HIF-1α diminished cellular energy, hypoxia-induced glycolytic gene expression, and angiogenesis not altering pro-angiogenic factors. Reduction of HIF-2α diminished hypoxia-induced pro-angiogenic factors, enhanced anti-angiogenic factors and attenuated angiogenesis not altering glycolytic gene expression. Reduction of both HIFs reduced cell survival, gene expression of glycolytic enzymes and pro-angiogenic factors as compared to the corresponding control. Finally, we identified the macrophage migration inhibitory factor (MIF) to be redundantly regulated by HIF-1 and HIF-2 and to be essential in the process of hypoxia-driven angiogenesis. Our results demonstrate a major impact of HIF-1 and HIF-2 on hypoxia-induced angiogenesis indicating distinct but also overlapping functions of HIF-1 and HIF-2. These findings open new possibilities for therapeutic approaches by specifically targeting the HIF-1 and HIF-2 or their target MIF.

Hahne M ，Schumann P ，Mursell M ，Strehl C ，Hoff P ，Buttgereit F ，Gaber T ... -  《-》