Bone Morphogenetic Protein Signaling is Required for RAD51-mediated Maintenance of Genome Integrity in Vascular Endothelial Cells

Overview

Journal Commun Biol

Specialty Biology

Date 2018 Oct 2

PMID 30272025

Citations 11

Authors

Sanna Vattulainen-Collanus

Mark Southwood

Xu Dong Yang

Stephen Moore

Prajakta Ghatpande

Nicholas W Morrell

Giorgio Lagna

Akiko Hata

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress.

Vasudevarao M, Posadas Pena D, Ihle M, Bongiovanni C, Maity P, Geissler D Nat Commun. 2025; 16(1):1708.

PMID: 39962064 PMC: 11832743. DOI: 10.1038/s41467-025-56993-6.

Shear stress unveils patient-specific transcriptional signatures in PAH: Towards personalized molecular diagnostics.

Wittig C, Konig J, Pan X, Aman J, Bogaard H, Yu P Theranostics. 2025; 15(5):1589-1605.

PMID: 39897541 PMC: 11780538. DOI: 10.7150/thno.105729.

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.

Prabhakar A, Kumar R, Wadhwa M, Ghatpande P, Zhang J, Zhao Z Nat Cardiovasc Res. 2024; 3(7):799-818.

PMID: 39196173 PMC: 11409862. DOI: 10.1038/s44161-024-00495-z.

Epithelial-mesenchymal interaction protects normal colonocytes from 4-HNE-induced phenotypic transformation.

Dupuy J, Cogo E, Fouche E, Gueraud F, Pierre F, Plaisancie P PLoS One. 2024; 19(4):e0302932.

PMID: 38669265 PMC: 11051638. DOI: 10.1371/journal.pone.0302932.

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension.

Isobe S, Nair R, Kang H, Wang L, Moonen J, Shinohara T Nat Commun. 2023; 14(1):7578.

PMID: 37989727 PMC: 10663616. DOI: 10.1038/s41467-023-43039-y.

References

Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X . Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010; 181(8):851-61. DOI: 10.1164/rccm.200908-1284OC. View

Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S . DNA Damage and Pulmonary Hypertension. Int J Mol Sci. 2016; 17(6). PMC: 4926518. DOI: 10.3390/ijms17060990. View

Lee S, Shroyer K, Markham N, Cool C, Voelkel N, Tuder R . Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998; 101(5):927-34. PMC: 508641. DOI: 10.1172/JCI1910. View

Hong Y, Liang H, Uzair-Ur-Rehman , Wang Y, Zhang W, Zhou Y . miR-96 promotes cell proliferation, migration and invasion by targeting PTPN9 in breast cancer. Sci Rep. 2016; 6:37421. PMC: 5114647. DOI: 10.1038/srep37421. View

Petermann E, Orta M, Issaeva N, Schultz N, Helleday T . Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol Cell. 2010; 37(4):492-502. PMC: 2958316. DOI: 10.1016/j.molcel.2010.01.021. View

Hurst L, Dunmore B, Long L, Crosby A, Al-Lamki R, Deighton J . TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun. 2017; 8:14079. PMC: 5241886. DOI: 10.1038/ncomms14079. View

Atkinson C, Stewart S, Upton P, Machado R, Thomson J, Trembath R . Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002; 105(14):1672-8. DOI: 10.1161/01.cir.0000012754.72951.3d. View

Wooderchak-Donahue W, McDonald J, OFallon B, Upton P, Li W, Roman B . BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013; 93(3):530-7. PMC: 3769931. DOI: 10.1016/j.ajhg.2013.07.004. View

Boucherat O, Peterlini T, Bourgeois A, Nadeau V, Breuils-Bonnet S, Boilet-Molez S . Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2018; 198(1):90-103. PMC: 6835039. DOI: 10.1164/rccm.201708-1751OC. View

10.

Hollnagel A, Oehlmann V, Heymer J, Ruther U, Nordheim A . Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J Biol Chem. 1999; 274(28):19838-45. DOI: 10.1074/jbc.274.28.19838. View

11.

Machado R, Aldred M, James V, Harrison R, Patel B, Schwalbe E . Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006; 27(2):121-32. DOI: 10.1002/humu.20285. View

12.

Soubrier F, Chung W, Machado R, Grunig E, Aldred M, Geraci M . Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D13-21. DOI: 10.1016/j.jacc.2013.10.035. View

13.

Davis B, Hilyard A, Lagna G, Hata A . SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008; 454(7200):56-61. PMC: 2653422. DOI: 10.1038/nature07086. View

14.

Courboulin A, Paulin R, Giguere N, Saksouk N, Perreault T, Meloche J . Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011; 208(3):535-48. PMC: 3058572. DOI: 10.1084/jem.20101812. View

15.

Long L, Ormiston M, Yang X, Southwood M, Graf S, Machado R . Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015; 21(7):777-85. PMC: 4496295. DOI: 10.1038/nm.3877. View

16.

Deanfield J, Halcox J, Rabelink T . Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115(10):1285-95. DOI: 10.1161/CIRCULATIONAHA.106.652859. View

17.

Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I . miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015; 309(6):C363-72. DOI: 10.1152/ajpcell.00149.2015. View

18.

Lane K, Talati M, Austin E, Hemnes A, Johnson J, Fessel J . Oxidative injury is a common consequence of BMPR2 mutations. Pulm Circ. 2011; 1(1):72-83. PMC: 3167174. DOI: 10.4103/2045-8932.78107. View

19.

Pu X, Wang Z, Klaunig J . Alkaline Comet Assay for Assessing DNA Damage in Individual Cells. Curr Protoc Toxicol. 2015; 65:3.12.1-3.12.11. DOI: 10.1002/0471140856.tx0312s65. View

20.

Bindra R, Schaffer P, Meng A, Woo J, Maseide K, Roth M . Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol. 2004; 24(19):8504-18. PMC: 516750. DOI: 10.1128/MCB.24.19.8504-8518.2004. View