Endothelial Progenitor Cells Stimulate Neonatal Lung Angiogenesis Through FOXF1-mediated Activation of BMP9/ACVRL1 Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Apr 20

PMID 35440116

Authors

Guolun Wang

Bingqiang Wen

Zicheng Deng

Yufang Zhang

Olena A Kolesnichenko

Vladimir Ustiyan

Arun Pradhan

Tanya V Kalin

Vladimir V Kalinichenko

Affiliations

Soon will be listed here.

Abstract

Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1 mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1 mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

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References

Bolte C, Whitsett J, Kalin T, Kalinichenko V . Transcription Factors Regulating Embryonic Development of Pulmonary Vasculature. Adv Anat Embryol Cell Biol. 2017; 228:1-20. DOI: 10.1007/978-3-319-68483-3_1. View

Pradhan A, Ustiyan V, Zhang Y, Kalin T, Kalinichenko V . Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response. Oncotarget. 2015; 7(2):1912-26. PMC: 4811506. DOI: 10.18632/oncotarget.6422. View

Bolte C, Ustiyan V, Ren X, Dunn A, Pradhan A, Wang G . Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia. Am J Respir Crit Care Med. 2020; 202(1):100-111. PMC: 7328311. DOI: 10.1164/rccm.201906-1232OC. View

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

Kim I, Zhou Y, Ramakrishna S, Hughes D, Solway J, Costa R . Functional characterization of evolutionarily conserved DNA regions in forkhead box f1 gene locus. J Biol Chem. 2005; 280(45):37908-16. DOI: 10.1074/jbc.M506531200. View

Chen X, Orriols M, Walther F, Laghmani E, Hoogeboom A, Hogen-Esch A . Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation. Front Physiol. 2017; 8:486. PMC: 5507999. DOI: 10.3389/fphys.2017.00486. View

Bolte C, Zhang Y, York A, Kalin T, Schultz J, Molkentin J . Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling. PLoS One. 2012; 7(11):e48713. PMC: 3493600. DOI: 10.1371/journal.pone.0048713. View

Johnson D, Berg J, Baldwin M, Gallione C, Marondel I, Yoon S . Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996; 13(2):189-95. DOI: 10.1038/ng0696-189. View

Wang X, Bhattacharyya D, Dennewitz M, Kalinichenko V, Zhou Y, Lepe R . Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes. Gene Expr. 2003; 11(3-4):149-62. PMC: 5991162. DOI: 10.3727/000000003108749044. View

10.

Bolte C, Flood H, Ren X, Jagannathan S, Barski A, Kalin T . FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy. Sci Rep. 2017; 7(1):10690. PMC: 5587533. DOI: 10.1038/s41598-017-11175-3. View

11.

Bolte C, Kalin T, Kalinichenko V . Molecular, cellular, and bioengineering approaches to stimulate lung regeneration after injury. Semin Cell Dev Biol. 2019; 100:101-108. DOI: 10.1016/j.semcdb.2019.10.006. View

12.

Niethamer T, Stabler C, Leach J, Zepp J, Morley M, Babu A . Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. Elife. 2020; 9. PMC: 7176435. DOI: 10.7554/eLife.53072. View

13.

Li W, Long L, Yang X, Tong Z, Southwood M, King R . Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice. Am J Respir Crit Care Med. 2020; 203(11):1419-1430. PMC: 8456542. DOI: 10.1164/rccm.202005-1761OC. View

14.

Suzuki Y, Ohga N, Morishita Y, Hida K, Miyazono K, Watabe T . BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. J Cell Sci. 2010; 123(Pt 10):1684-92. DOI: 10.1242/jcs.061556. View

15.

Kalinichenko V, Gusarova G, Shin B, Costa R . The forkhead box F1 transcription factor is expressed in brain and head mesenchyme during mouse embryonic development. Gene Expr Patterns. 2003; 3(2):153-8. DOI: 10.1016/s1567-133x(03)00010-3. View

16.

Guo M, Du Y, Gokey J, Ray S, Bell S, Adam M . Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. Nat Commun. 2019; 10(1):37. PMC: 6318311. DOI: 10.1038/s41467-018-07770-1. View

17.

Lim L, Kalinichenko V, Whitsett J, Costa R . Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele. Am J Physiol Lung Cell Mol Physiol. 2002; 282(5):L1012-22. DOI: 10.1152/ajplung.00371.2001. View

18.

Shovlin C, Hughes J, Tuddenham E, Temperley I, Perembelon Y, Scott J . A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet. 1994; 6(2):205-9. DOI: 10.1038/ng0294-205. View

19.

Goda C, Balli D, Black M, Milewski D, Le T, Ustiyan V . Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway. PLoS Genet. 2020; 16(4):e1008692. PMC: 7173935. DOI: 10.1371/journal.pgen.1008692. View

20.

Ustiyan V, Zhang Y, Perl A, Whitsett J, Kalin T, Kalinichenko V . β-catenin and Kras/Foxm1 signaling pathway are critical to restrict Sox9 in basal cells during pulmonary branching morphogenesis. Dev Dyn. 2016; 245(5):590-604. PMC: 4844868. DOI: 10.1002/dvdy.24393. View