BioProject

Patients with a heterozygous mutation in Endoglin (Eng) suffer from hereditary hemorrhagic telangiectasia (HHT), a condition characterized by the development of arteriovenous malformations (AVMs) across various organs, leading to significant bleeding, blood abnormalities, and anemia. More...

Patients with a heterozygous mutation in Endoglin (Eng) suffer from hereditary hemorrhagic telangiectasia (HHT), a condition characterized by the development of arteriovenous malformations (AVMs) across various organs, leading to significant bleeding, blood abnormalities, and anemia. Eng is a transmembrane protein and an accessory receptor for transforming growth factor-β (TGF-β) and is therefore essential for maintaining normal vascular architecture. Despite extensive research linking Eng deficiency to AVMs, the precise mechanisms driving this association remain poorly understood. In addition, the role of the bone marrow, a primary source of immune and other blood cells, in the context of endothelial Eng (EC-Eng) deficiency has yet to be explored. In this study, we demonstrate that bone marrow blood vessels conditionally deficient in Eng undergo a temporally orchestrated remodeling process over four weeks, characterized by distinct proliferative and resolution phases. We detail the specific phases of this remodeling, including angiogenic set points, the involvement of the beta integrin family, and modulation of vascular integrity. Furthermore, we explore the impact on the hematopoietic stem and progenitor cell (HSPC) compartment and the resultant changes in circulating blood cells. Using a conditional heterozygous deficient EC-Eng mouse model, we observe significant similarities to phenotypes described in the cKO line, which may ultimately be detrimental in patients with HHT. Taken together, using a combination of different in vivo approaches, our research proposes that very low levels of Eng expression in the endothelium may drive critical vascular remodeling in the bone marrow, sharing mechanisms with early vascular processes leading to AVM formation. Overall design: To analyze the effects of endothelial Endoglin deficiency, we generated the Cdh5:CreERT2-Engf/f mouse line. The Enff/f mous line has been described previously and contains loxP sites flanking exons five and six of the endoglin gene. For this project, we induced the KO by using tamoxifen injections when mice reached 8 weeks of age. Flow cytometry and cell sorting were performed, with endothelial cells from bone marrow being defined as CD31+, CD45,ter119-. These cells were isolated directly into lysis buffer. We performed gene expression profiling analysis using data obtained from RNAseq of WT and KO femurs at 2 different timepoints (2 and 4 weeks after KO induction) Less...