Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells

• Published in: Communications biology Vol. 1; no. 1; p. 149
• Main Authors: Vattulainen-Collanus, Sanna, Southwood, Mark, Yang, Xu Dong, Moore, Stephen, Ghatpande, Prajakta, Morrell, Nicholas W., Lagna, Giorgio, Hata, Akiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2018; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 13/89; 38/39; 38/90; 631/337/1427/2566; 631/80/86/2370; 692/4019/592/75/593/1920; 82/80; Animal models; Biology; Biomedical and Life Sciences; Blood vessels; Bone morphogenetic protein receptor type II; Bone morphogenetic proteins; Cell culture; Cell death; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA repair; Endothelial cells; Genomes; Hemorrhage; Hereditary hemorrhagic telangiectasia; Homeostasis; Hypertension; Life Sciences; Mutation; Phenotypes; Pulmonary hypertension; Replication; Signal transduction
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-018-0152-1

The integrity of blood vessels is fundamental to vascular homeostasis. Inactivating mutations in the bone morphogenetic protein (BMP) receptor type II (BMPR2) gene cause hereditary vascular disorders, including pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, suggesting that BMPR2 and its downstream signaling pathway are pivotal to the maintenance of vascular integrity through an unknown molecular mechanism. Here we report that inactivation of BMPR2 in pulmonary vascular endothelial cells results in a deficit of RAD51, an enzyme essential for DNA repair and replication. Loss of RAD51, which causes DNA damage and cell death, is also detected in animal models and human patients with pulmonary arterial hypertension. Restoration of BMPR2 or activation of the BMP signaling pathway rescues RAD51 and prevents DNA damage. This is an unexpected role of BMP signaling in preventing the accumulation of DNA damage and the concomitant loss of endothelial integrity and vascular remodeling associated with vascular disorders. Sanna Vattulainen-Collanus et al. report that mutations in the BMPR2 gene, which is associated with pulmonary arterial hypertension, result in a deficit of RAD51 and altered DNA repair and replication. They were able to rescue the RAD51-deficient phenotype by restoring BMPR2 activity in cell culture.