Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2011

Open Access 01-12-2011 | Research

Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

Authors: Lunyin Yu, Charles A Hales

Published in: Respiratory Research | Issue 1/2011

Login to get access

Abstract

Background

CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood.

Methods

In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats.

Results

We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats.

Conclusions

The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.
Appendix
Available only for authorised users
Literature
1.
Stenmark R, Fagan K, Frid MG: Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006, 99: 675-691. 10.1161/01.RES.0000243584.45145.3f.CrossRefPubMed
2.
Jeffery TK, Wanstall JC: Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol Ther. 2001, 92: 1-20. 10.1016/S0163-7258(01)00157-7.CrossRefPubMed
3.
Rabinovitch M: Pulmonary vascular remodeling in hypoxic pulmonary hypertension. Hypoxic Pulmonary Vasoconstriction Cellular and Molecular Mechanisms. 2004, J. Yuan, Kluwer Academic Publishers. Boston, MA, Chap 23: 403-418. full_text.CrossRef
4.
Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM: The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med. 2003, 167 (12): 1676-86. 10.1164/rccm.200301-071OC.CrossRefPubMed
5.
Fernandez EJ, Lolis E: Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol. 2002, 42: 469-99. 10.1146/annurev.pharmtox.42.091901.115838.CrossRefPubMed
6.
Laing K, Secombes C: Chemokines. Dev Comp Immunol. 2004, 28 (5): 443-60. 10.1016/j.dci.2003.09.006.CrossRefPubMed
7.
Burger JA, Kipps TJ: CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006, 107 (5): 1761-7. 10.1182/blood-2005-08-3182.CrossRefPubMed
8.
Schober A, Zernecke A: Chemokines in vascular remodeling. Thromb Haemost. 2007, 97 (5): 730-7.PubMed
9.
Petit I, Jin D, Rafii S: The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 2007, 28 (7): 299-307. 10.1016/j.it.2007.05.007.CrossRefPubMedPubMedCentral
10.
Nemenoff RA, Simpson PA, Furgeson SB, Kaplan-Albuquerque N, Crossno J, Garl PJ, Cooper J, Weiser-Evans MC: Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha. Circ Res. 2008, 102 (9): 1036-45. 10.1161/CIRCRESAHA.107.169896.CrossRefPubMed
11.
Karshovska E, Zagorac D, Zernecke A, Weber C, Schober A: A small molecule CXCR4 antagonist inhibits neointima formation and smooth muscle progenitor cell mobilization after arterial injury. J Thromb Haemost. 2008, 6 (10): 1812-5. 10.1111/j.1538-7836.2008.03086.x.CrossRefPubMed
12.
Zernecke A, Schober A, Bot I, von Hundelshausen P, Liehn EA, Möpps B, Mericskay M, Gierschik P, Biessen EA, Weber C: SDF-1alpha/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells. Circ Res. 2005, 96 (7): 784-91. 10.1161/01.RES.0000162100.52009.38.CrossRefPubMed
13.
Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, Karibe A, Kagaya Y, Ishii N, Sugamura K, Shimokawa H: Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res. 2009, 81: 226-234. 10.1093/cvr/cvn244.CrossRefPubMed
14.
Tiveron MC, Cremer H: CXCL12/CXCR4 signalling in neuronal cell migration. Curr Opin Neurobiol. 2008, 18 (3): 237-44. 10.1016/j.conb.2008.06.004.CrossRefPubMed
15.
Vandercappellen J, Van Damme J, Struyf S: The role of CXC chemokines and their receptors in cancer. Cancer Lett. 2008, 267 (2): 226-44. 10.1016/j.canlet.2008.04.050.CrossRefPubMed
16.
Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ, Zhang J, Ratajczak J, Ratajczak MZ: CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol. 2004, 35 (3): 233-45. 10.1023/B:HIJO.0000032355.66152.b8.CrossRefPubMed
17.
Day CE, Guillen C, Willars GB, Wardlaw AJ: Characterization of the migration of lung and blood T cells in response CXCL12 in a three-dimensional matrix. Immunology. 2010, 130 (4): 564-71. 10.1111/j.1365-2567.2010.03257.x.CrossRefPubMedPubMedCentral
18.
Agle KA, Vongsa RA, Dwinell MB: Calcium mobilization triggered by the chemokine CXCL12 regulates migration in wounded intestinal epithelial monolayers. J Biol Chem. 2010, 285 (21): 16066-75. 10.1074/jbc.M109.061416.CrossRefPubMedPubMedCentral
19.
Esencay M, Newcomb EW, Zagzag D: HGF upregulates CXCR4 expression in gliomas via NF-kappaB: implications for glioma cell migration. J Neurooncol. 2010, 99 (1): 33-40. 10.1007/s11060-010-0111-2.CrossRefPubMedPubMedCentral
20.
Cho SY, Xu M, Roboz J, Lu M, Mascarenhas J, Hoffman R: The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms. Cancer Res. 2010, 70 (8): 3402-10. 10.1158/0008-5472.CAN-09-3977.CrossRefPubMed
21.
Rehimi R, Khalida N, Yusuf F, Morosan-Puopolo G, Brand-Saberi B: A novel role of CXCR4 and SDF-1 during migration of cloacal muscle precursors. Dev Dyn. 2010, 239 (6): 1622-31. 10.1002/dvdy.22288.CrossRefPubMed
22.
Stumm R, Höllt V: CXC chemokine receptor 4 regulates neuronal migration and axonal pathfinding in the developing nervous system: implications for neuronal regeneration in the adult brain. J Mol Endocrinol. 2007, 38 (3): 377-82. 10.1677/JME-06-0032.CrossRefPubMed
23.
Nervi B, Link DC, DiPersio JF: Cytokines and hematopoietic stem cell mobilization. J Cell Biochem. 2006, 99 (3): 690-705. 10.1002/jcb.21043.CrossRefPubMed
24.
Hamed S, Brenner B, Abassi Z, Aharon A, Daoud D, Roguin A: Hyperglycemia and Oxidized-LDL exert a deleterious effect on Endothelial Progenitor Cell migration in Type 2 Diabetes Mellitus. Thromb Res. 2010, 126 (3): 166-74. 10.1016/j.thromres.2010.03.002.CrossRefPubMed
25.
Yu J, Li M, Qu Z, Yan D, Li D, Ruan Q: SDF-1/CXCR4-mediated migration of transplanted bone marrow stromal cells toward areas of heart myocardial infarction through activation of PI3K/Akt. J Cardiovasc Pharmacol. 2010, 55 (5): 496-505.PubMed
26.
Young KC, Torres E, Hatzistergos KE, Hehre D, Suguihara C, Hare JM: Inhibition of the SDF-1/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension. Circ Res. 2009, 104 (11): 1293-301. 10.1161/CIRCRESAHA.109.197533.CrossRefPubMedPubMedCentral
27.
Gambaryan N, Perros F, Montani D, Cohen-Kaminsky S, Mazmanian M, Renaud JF, Simonneau G, Lombet A, Humbert M: Targeting of c-kit+ hematopoietic progenitor cells prevents hypoxic pulmonary hypertension. Eur Respir J.
28.
Spees JL, Whitney MJ, Sullivan DE, Lasky JA, Laboy M, Ylostalo J, Prockop DJ: Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J. 2008, 22 (4): 1226-36. 10.1096/fj.07-8076com.CrossRefPubMed
29.
Kroeger K, Collins M, Ugozzoli L: The Preparation of Primary Hematopoietic Cell Cultures From Murine Bone Marrow for Electroporation. J Vis Exp. 2009, 23:
30.
Li LH, McCarthy P, Hui SW: High-efficiency electrotransfection of human primary hematopoietic stem cells. The FASEB Journal. 2001, 15: 586-588.PubMed
31.
von Levetzow G, Spanholtz J, Beckmann J, Fischer J, Kögler G, Wernet P, Punzel M, Giebel B: Nucleofection, an efficient nonviral method to transfer genes into human hematopoietic stem and progenitor cells. Stem Cells Dev. 2006, 15 (2): 278-85. 10.1089/scd.2006.15.278.CrossRefPubMed
32.
Helledie T, Nurcombe V, Cool SM: A Simple and Reliable Electroporation Method for Human Bone Marrow Mesenchymal Stem Cells. Stem Cells Dev. 2008, 17 (4): 837-48. 10.1089/scd.2007.0209.CrossRefPubMed
33.
Narayanan R, Jastreboff MM, Chiu CF, Bertino JR: In vivo expression of a nonselected gene transferred into murine hematopoietic stem cells by electroporation. Biochem Biophys Res Commun. 1986, 141 (3): 1018-24. 10.1016/S0006-291X(86)80146-2.CrossRefPubMed
34.
Hales CA, Kradin RL, Brandstetter RD, Zhu YJ: Impairment of hypoxic pulmonary artery remodeling by heparin in mice. Am Rev Respir Dis. 1983, 128: 747-51.PubMed
35.
Yu L, Quinn DA, Garg HG, Hales CA: Cyclin-dependent kinase inhibitor p27Kip1, but not p21WAF1/Cip1, is required for inhibition of hypoxia-induced pulmonary hypertension and remodeling by heparin in mice. Circ Res. 2005, 97: 937-45. 10.1161/01.RES.0000188211.83193.1a.CrossRefPubMed
36.
Yu L, Quinn DA, Garg HG, Hales CA: Deficiency of NHE1 Gene Prevents Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling. Am. J. Respir. Crit. Care Med. 2008, 177 (11): 1276-84. 10.1164/rccm.200710-1522OC.CrossRefPubMedPubMedCentral
37.
Quinn DA, Du HK, Thompson BT, Hales CA: Amiloride analogs inhibit chronic hypoxic pulmonary hypertension. Am J Respir Crit Care Med. 1998, 157: 1263-8.CrossRefPubMed
38.
Yu L, Quinn DA, Garg HG, Hales CA: Heparin Inhibits Pulmonary Artery Smooth Muscle Cell Proliferation through GEF-H1/RhoA/ROCK/p27. Am J Respir Cell Mol Biol.
39.
Yu L, Quinn DA, Garg HG, Hales CA: Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension. Biochem Biophys Res Commun. 2006, 345: 1565-72. 10.1016/j.bbrc.2006.05.060.CrossRefPubMed
40.
Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, Morrell NW: Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2009, 180 (8): 780-7. 10.1164/rccm.200810-1662OC.CrossRefPubMedPubMedCentral
41.
Davie NJ, Crossno JT, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, Stenmark KR: Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol. 2004, 286 (4): L668-78. 10.1152/ajplung.00108.2003.CrossRefPubMed
42.
Hayashida K, Fujita J, Miyake Y, Kawada H, Ando K, Ogawa S, Fukuda K: Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension. Chest. 2005, 127 (5): 1793-8. 10.1378/chest.127.5.1793.CrossRefPubMed
43.
Castellani C, Padalino M, China P, Fedrigo M, Frescura C, Milanesi O, Stellin G, Thiene G, Angelini A: Bone-marrow-derived CXCR4-positive tissue-committed stem cell recruitment in human right ventricular remodeling. Hum Pathol. 2010, 41 (11): 1566-76. 10.1016/j.humpath.2009.12.017.CrossRefPubMed
44.
Jujo K, Hamada H, Iwakura A, Thorne T, Sekiguchi H, Clarke T, Ito A, Misener S, Tanaka T, Klyachko E, Kobayashi K, Tongers J, Roncalli J, Tsurumi Y, Hagiwara N, Losordo DW: CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci USA. 2010, 107 (24): 11008-13. 10.1073/pnas.0914248107.CrossRefPubMedPubMedCentral
45.
Dai M, Yang Y, Omelchenko I, Nuttall AL, Kachelmeier A, Xiu R, Shi X: Bone Marrow Cell Recruitment Mediated by Inducible Nitric Oxide Synthase/Stromal Cell-Derived Factor-1{alpha} Signaling Repairs the Acoustically Damaged Cochlear Blood-Labyrinth Barrier. Am J Pathol. 2010, 177 (6): 3089-99. 10.2353/ajpath.2010.100340.CrossRefPubMedPubMedCentral
46.
Wyss BK, Donnelly AF, Zhou D, Sinn AL, Pollok KE, Goebel WS: Enhanced homing and engraftment of fresh but not ex vivo cultured murine marrow cells in submyeloablated hosts following CD26 inhibition by Diprotin A. Exp Hematol. 2009, 37 (7): 814-23. 10.1016/j.exphem.2009.03.005.CrossRefPubMedPubMedCentral
47.
Ohno N, Kajiume T, Sera Y, Sato T, Kobayashi M: Short-term culture of umbilical cord blood-derived CD34 cells enhances engraftment into NOD/SCID mice through increased CXCR4 expression. Stem Cells Dev. 2009, 18 (8): 1221-6. 10.1089/scd.2008.0298.CrossRefPubMed
48.
Juarez J, Dela Pena A, Baraz R, Hewson J, Khoo M, Cisterne A, Fricker S, Fujii N, Bradstock KF, Bendall LJ: CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia. 2007, 21 (6): 1249-57. 10.1038/sj.leu.2404684.CrossRefPubMed
49.
Monaco G, Konopleva M, Munsell M, Leysath C, Wang RY, Jackson CE, Korbling M, Estey E, Belmont J, Andreeff M: Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival. Stem Cells. 2004, 22 (2): 188-201. 10.1634/stemcells.22-2-188.CrossRefPubMed
50.
Kang Y, Chen BJ, Deoliveira D, Mito J, Chao NJ: Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model. PLoS One. 2010, 5 (6): e11316-10.1371/journal.pone.0011316.CrossRefPubMedPubMedCentral
Metadata
Title
Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats
Authors
Lunyin Yu
Charles A Hales
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2011
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-12-21

Other articles of this Issue 1/2011

Respiratory Research 1/2011 Go to the issue

Research

Adverse health consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial

Research

Differences in allergen-induced T cell activation between allergic asthma and rhinitis: Role of CD28, ICOS and CTLA-4

Research

Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma

Research

Physiologic and molecular consequences of endothelial Bmpr2 mutation

Research

Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts

Review

TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits