C-type natriuretic peptide/cGMP/FoxO3 signaling attenuates hyperproliferation of pericytes from patients with pulmonary arterial hypertension.
Humans
Pericytes
/ metabolism
Natriuretic Peptide, C-Type
/ metabolism
Cyclic GMP
/ metabolism
Signal Transduction
Forkhead Box Protein O3
/ metabolism
Cell Proliferation
Male
Female
Pulmonary Arterial Hypertension
/ metabolism
Middle Aged
Hypertension, Pulmonary
/ metabolism
Adult
Receptors, Atrial Natriuretic Factor
/ metabolism
Cells, Cultured
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
06 Jun 2024
06 Jun 2024
Historique:
received:
27
07
2023
accepted:
23
05
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
6
6
2024
Statut:
epublish
Résumé
Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.
Identifiants
pubmed: 38844781
doi: 10.1038/s42003-024-06375-3
pii: 10.1038/s42003-024-06375-3
doi:
Substances chimiques
Natriuretic Peptide, C-Type
127869-51-6
Cyclic GMP
H2D2X058MU
Forkhead Box Protein O3
0
FOXO3 protein, human
0
Receptors, Atrial Natriuretic Factor
EC 4.6.1.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
693Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : DA2462/1-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : KU 1037/8-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : KU 1037/12-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC 1525, 45398101
Organisme : Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)
ID : 2021_EKEA.131
Informations de copyright
© 2024. The Author(s).
Références
Humbert, M. et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur. Respir. J. 53, 1801887 (2019).
pubmed: 30545970
pmcid: 6351340
doi: 10.1183/13993003.01887-2018
Humbert, M. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, 13S–24S (2004).
pubmed: 15194174
doi: 10.1016/j.jacc.2004.02.029
Yuan, K. et al. Lung pericytes in pulmonary vascular physiology and pathophysiology. Compr. Physiol. 11, 2227–2247 (2021).
pubmed: 34190345
pmcid: 10507675
doi: 10.1002/cphy.c200027
Schermuly, R. T., Ghofrani, H. A., Wilkins, M. R. & Grimminger, F. Mechanisms of disease: pulmonary arterial hypertension. Nat. Rev. Cardiol. 8, 443–455 (2011).
pubmed: 21691314
pmcid: 7097518
doi: 10.1038/nrcardio.2011.87
He, S., Zhu, T. & Fang, Z. The role and regulation of pulmonary artery smooth muscle cells in pulmonary hypertension. Int. J. Hypertens. 2020, 1478291 (2020).
pubmed: 32850144
pmcid: 7441461
doi: 10.1155/2020/1478291
Bordenave, J. et al. Lineage tracing reveals the dynamic contribution of pericytes to the blood vessel remodeling in pulmonary hypertension. Arterioscler. Thromb. Vasc. Biol. 40, 766–782 (2020).
pubmed: 31969018
doi: 10.1161/ATVBAHA.119.313715
Yuan, K. et al. Increased pyruvate dehydrogenase kinase 4 expression in lung pericytes is associated with reduced endothelial–pericyte interactions and small vessel loss in pulmonary arterial hypertension. Am. J. Pathol. 186, 2500–2514 (2016).
pubmed: 27456128
pmcid: 5012507
doi: 10.1016/j.ajpath.2016.05.016
Ricard, N. et al. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129, 1586–1597 (2014).
pubmed: 24481949
doi: 10.1161/CIRCULATIONAHA.113.007469
Yuan, K. et al. Mural cell SDF1 signaling is associated with the pathogenesis of pulmonary arterial hypertension. Am. J. Respir. Cell. Mol Biol. 62, 747–759 (2020).
pubmed: 32084325
pmcid: 7258825
doi: 10.1165/rcmb.2019-0401OC
Yuan, K. et al. Loss of endothelium-derived wnt5a is associated with reduced pericyte recruitment and small vessel loss in pulmonary arterial hypertension. Circulation 139, 1710–1724 (2019).
pubmed: 30586764
pmcid: 6443444
doi: 10.1161/CIRCULATIONAHA.118.037642
Bubb, K. J. et al. Endothelial C-type natriuretic peptide is a critical regulator of angiogenesis and vascular remodeling. Circulation 139, 1612–1628 (2019).
pubmed: 30586761
pmcid: 6438487
doi: 10.1161/CIRCULATIONAHA.118.036344
Moyes, A. J. et al. Endothelial C-type natriuretic peptide maintains vascular homeostasis. J. Clin. Investig. 124, 4039–4051 (2014).
pubmed: 25105365
pmcid: 4151218
doi: 10.1172/JCI74281
Spiranec, K. et al. Endothelial C-type natriuretic peptide acts on pericytes to regulate microcirculatory flow and blood pressure. Circulation 138, 494–508 (2018).
pubmed: 29626067
doi: 10.1161/CIRCULATIONAHA.117.033383
Itoh, T. et al. C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 170, 1204–1211 (2004).
pubmed: 15333333
doi: 10.1164/rccm.200404-455OC
Nawa, N. et al. Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension. Mol. Ther. Methods Clin. Dev. 3, 16044 (2016).
pubmed: 27419193
pmcid: 4934588
doi: 10.1038/mtm.2016.44
Chrisman, T. D. & Garbers, D. L. Reciprocal antagonism coordinates C-type natriuretic peptide and mitogen-signaling pathways in fibroblasts. J. Biol. Chem. 274, 4293–4299 (1999).
pubmed: 9933630
doi: 10.1074/jbc.274.7.4293
Solinc, J. et al. The platelet-derived growth factor pathway in pulmonary arterial hypertension: still an interesting target? Life (Basel) 12, 658 (2022).
pubmed: 35629326
Savai, R. et al. Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat. Med. 20, 1289–1300 (2014).
pubmed: 25344740
doi: 10.1038/nm.3695
Kudryashova, T. V. et al. Noncanonical HIPPO/MST signaling via BUB3 and FOXO drives pulmonary vascular cell growth and survival. Circ. Res. 130, 760–778 (2022).
pubmed: 35124974
pmcid: 8897250
doi: 10.1161/CIRCRESAHA.121.319100
Xie, Q., Chen, J. & Yuan, Z. Post-translational regulation of FOXO. Acta Biochim. Biophys. Sin. (Shanghai) 44, 897–901 (2012).
pubmed: 22935512
doi: 10.1093/abbs/gms067
Al-Tamari, H. M. et al. FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. EMBO Mol. Med. 10, 276–293 (2018).
pubmed: 29217661
doi: 10.15252/emmm.201606261
Hu, C. et al. ROCK1 promotes migration and invasion of non‑small‑cell lung cancer cells through the PTEN/PI3K/FAK pathway. Int. J. Oncol. 55, 833–844 (2019).
pubmed: 31485605
pmcid: 6741846
Teichert, M. et al. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat. Commun. 8, 16106 (2017).
pubmed: 28719590
pmcid: 5520106
doi: 10.1038/ncomms16106
Fragoso, R. & Barata, J. T. Kinases, tails and more: regulation of PTEN function by phosphorylation. Methods 77-78, 75–81 (2015).
pubmed: 25448482
doi: 10.1016/j.ymeth.2014.10.015
Sawada, N. et al. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem. Biophys. Res. Commun. 280, 798–805 (2001).
pubmed: 11162591
doi: 10.1006/bbrc.2000.4194
Das, A., Xi, L. & Kukreja, R. C. Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. J. Biol. Chem. 283, 29572–29585 (2008).
pubmed: 18723505
pmcid: 2570896
doi: 10.1074/jbc.M801547200
Novoyatleva, T. et al. Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2. Commun. Biol. 4, 1002 (2021).
pubmed: 34429509
pmcid: 8385080
doi: 10.1038/s42003-021-02531-1
Werner, F. et al. Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice. Basic Res. Cardiol. 111, 22 (2016).
pubmed: 26909880
pmcid: 4766231
doi: 10.1007/s00395-016-0541-x
Kuhn, M. Molecular physiology of membrane guanylyl cyclase receptors. Physiol. Rev. 96, 751–804 (2016).
pubmed: 27030537
doi: 10.1152/physrev.00022.2015
Klinger, J. R. et al. C-type natriuretic peptide expression and pulmonary vasodilation in hypoxia-adapted rats. Am. J. Physiol. 275, L645–L652 (1998).
pubmed: 9755096
Kimura, T. et al. C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice. Respir. Res. 17, 19 (2016).
pubmed: 26895702
pmcid: 4761143
doi: 10.1186/s12931-016-0335-6
Selimovic, N. et al. Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension. Eur. Respir. J. 34, 662–668 (2009).
pubmed: 19324949
doi: 10.1183/09031936.00174908
Garrison, A. T., Bignold, R. E., Wu, X. & Johnson, J. R. Pericytes: the lung-forgotten cell type. Front. Physiol. 14, 1150028 (2023).
pubmed: 37035669
pmcid: 10076600
doi: 10.3389/fphys.2023.1150028
Schermuly, R. T. et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Investig. 115, 2811–2821 (2005).
pubmed: 16200212
pmcid: 1236676
doi: 10.1172/JCI24838
Ten Freyhaus, H. et al. Genetic ablation of PDGF-dependent signaling pathways abolishes vascular remodeling and experimental pulmonary hypertension. Arterioscler. Thromb. Vasc. Biol. 35, 1236–1245 (2015).
pubmed: 25745058
pmcid: 5588904
doi: 10.1161/ATVBAHA.114.304864
Li, P. et al. Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ. Res. 102, 185–192 (2008).
pubmed: 17991884
doi: 10.1161/CIRCRESAHA.107.157677
Gong, K. et al. cGMP inhibits TGF-beta signaling by sequestering Smad3 with cytosolic beta2-tubulin in pulmonary artery smooth muscle cells. Mol. Endocrinol. 25, 1794–1803 (2011).
pubmed: 21868450
pmcid: 3182417
doi: 10.1210/me.2011-1009
Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).
pubmed: 11057895
doi: 10.1016/S0092-8674(00)00114-8
Wilkins, M. R. et al. Positioning imatinib for pulmonary arterial hypertension: a phase I/II design comprising dose finding and single-arm efficacy. Pulm. Circ. 11, 20458940211052823 (2021).
pubmed: 34868551
pmcid: 8642118
doi: 10.1177/20458940211052823
Chen, G. et al. C-type natriuretic peptide attenuates LPS-induced endothelial activation: involvement of p38, Akt, and NF-kappaB pathways. Amino Acids 46, 2653–2663 (2014).
pubmed: 25096521
doi: 10.1007/s00726-014-1816-x
Lin, J. E. et al. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology 138, 241–254 (2010).
pubmed: 19737566
doi: 10.1053/j.gastro.2009.08.064
Chen, C. Y., Chen, J., He, L. & Stiles, B. L. PTEN: tumor suppressor and metabolic regulator. Front. Endocrinol. (Lausanne) 9, 338 (2018).
pubmed: 30038596
doi: 10.3389/fendo.2018.00338
Kaiser, R. et al. Associations of circulating natriuretic peptides with haemodynamics in precapillary pulmonary hypertension. Respir. Med. 109, 1213–1223 (2015).
pubmed: 26194624
doi: 10.1016/j.rmed.2015.02.014
Schneider, E. L., Carreras, C. W., Reid, R., Ashley, G. W. & Santi, D. V. A long-acting C-natriuretic peptide for achondroplasia. Proc. Natl Acad. Sci. USA 119, e2201067119 (2022).
pubmed: 35858423
pmcid: 9335275
doi: 10.1073/pnas.2201067119
Yuan, K. et al. Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am. J. Pathol. 185, 69–84 (2015).
pubmed: 25447046
pmcid: 4278244
doi: 10.1016/j.ajpath.2014.09.013
Dabral, S. et al. A RASSF1A-HIF1alpha loop drives Warburg effect in cancer and pulmonary hypertension. Nat. Commun. 10, 2130 (2019).
pubmed: 31086178
pmcid: 6513860
doi: 10.1038/s41467-019-10044-z