The impact of endothelial restricted hypoxia pathway proteins (PHD2 and endoglin) on the hematopoietic system and its bone marrow niche

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Sufficient oxygen pressure is required for our organs to function properly. Conversely, insufficient oxygen supply (hypoxia) is a prominent feature in various physiological and pathological processes. The central mediators during deprived oxygen pressure are hypoxia inducible factors (HIFs), whereas their downstream effects are tightly regulated by oxygen-dependent HIF prolyl hydroxylases (PHDs). For this grant proposal, we collected robust sets of preliminary data revealing central roles for endothelial PHD2 and endoglin, in maintaining the integrity of the BM niche and the hematopoietic stem cell (HSC) compartment. In a first aim, we will further characterize the loss of EC-PHD2 and evaluate its effect on bone metabolism, vessel stability and maintenance of the HSC compartment under steady state conditions and after non-lethal irradiation stress. In a second aim, we will unravel the intriguing and protective role of EC-restricted endoglin/CD105 in controlling the HSC compartment and its BM niche. This project will not only provide novel insights into the role of hypoxia pathway proteins in the bone/BM endothelial cells and its interaction with the BM environment; our findings will also raise awareness when it comes to the use of broad spectrum PHD inhibitors to treat patients.