title: The impact of chronic intermittent hypoxia on hematopoiesis and the bone marrow microenvironment.
abstract: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder which is associated with patient morbidity and an elevated risk of developing hypertension and cardiovascular diseases. There is ample evidence for the involvement of bone marrow (BM) cells in the pathophysiology of cardiovascular diseases but a connection between OSA and modulation of the BM microenvironment had not been established. Here, we studied how chronic intermittent hypoxia (CIH) affected hematopoiesis and the BM microenvironment, in a rat model of OSA. We show that CIH followed by normoxia increases the bone marrow hypoxic area, increases the number of multipotent hematopoietic progenitors (CFU assay), promotes erythropoiesis, and increases monocyte counts. In the BM microenvironment of CIH-subjected animals, the number of VE-cadherin-expressing blood vessels, particularly sinusoids, increased, accompanied by increased smooth muscle cell coverage, while vWF-positive vessels decreased. Molecularly, we investigated the expression of endothelial cell-derived genes (angiocrine factors) that could explain the cellular phenotypes. Accordingly, we observed an increase in colony-stimulating factor 1, vascular endothelium growth factor, delta-like 4, and angiopoietin-1 expression. Our data shows that CIH induces vascular remodeling in the BM microenvironment, which modulates hematopoiesis, increasing erythropoiesis, and circulating monocytes. Our study reveals for the first time the effect of CIH in hematopoiesis and suggests that hematopoietic changes may occur in OSA patients.
authors: Angiogenesis Lab, CIPM, Portuguese Institute of Oncology, IPOLFG, EPE, Lisbon, Portugal.|Instituto de Medicina Molecular, Edificio Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors: Inês
authors: I
authors: Alvarez-Martins
authors: Angiogenesis Lab, CIPM, Portuguese Institute of Oncology, IPOLFG, EPE, Lisbon, Portugal.
authors: Leonor
authors: L
authors: Remédio
authors: Angiogenesis Lab, CIPM, Portuguese Institute of Oncology, IPOLFG, EPE, Lisbon, Portugal.|Instituto de Medicina Molecular, Edificio Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors: Inês
authors: I
authors: Matias
authors: CEDOC, Nova Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.|Translational Pharmacology Lab, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.
authors: Lucília N
authors: LN
authors: Diogo
authors: CEDOC, Nova Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.|Translational Pharmacology Lab, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.
authors: Emília C
authors: EC
authors: Monteiro
authors: Instituto de Medicina Molecular, Edificio Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisbon, Portugal. sergiodias@medicina.ulisboa.pt.
authors: Sérgio
authors: S
authors: Dias
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D006410:Hematopoiesis; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D055153:Stem Cell Niche; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A; D016173:Macrophage Colony-Stimulating Factor
keywords: Bone marrow microenvironment; Chronic intermittent hypoxia; Hematopoiesis; Vascular niche