p53 activation in bone marrow vascular niche compromises hematopoiesis via reorganization of vascular and perivascular niches

p53 is activated in blood vessels by various stresses, such as hypoxia, inflammation and aging, and contributes to tissue dysfunction and metabolic abnormalities; however, it remains unclear whether such stresses affect hematopoiesis via acting on bone marrow (BM) vascular niche. Here, we found that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatment, which induced depletion of BM vessels. Conditional activation of p53 in VE-Cadherin+ vascular niche cells by deleting Mdm2 induced expression of p53 target genes, resulting in dilation and apoptosis of vascular endothelial cells and reduction in perivascular mesenchymal stromal cells. Consequently, hematopoietic stem cells (HSCs) failed to maintain dormancy, showed mobilization to the periphery, and were significantly depleted. Our findings indicate that various hematopoietic insults affect HSCs not only directly, but also indirectly via affecting vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.