High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia‑induced rat model of pulmonary arterial hypertension

Zhang,Tingting; Kawaguchi,Nanako; Hayama,Emiko; Furutani,Yoshiyuki; Nakanishi,Toshio

doi:10.3892/etm.2018.6027

High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia‑induced rat model of pulmonary arterial hypertension

Authors:
- Tingting Zhang
- Nanako Kawaguchi
- Emiko Hayama
- Yoshiyuki Furutani
- Toshio Nakanishi
View Affiliations

Affiliations: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo 162‑8666, Japan
Published online on: April 3, 2018 https://doi.org/10.3892/etm.2018.6027
Pages: 4615-4622
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome. C‑X‑C chemokine receptor type 4 (CXCR4) is known to serve a key role in recruiting mesenchymal stem cells (MSCs) from the bone marrow. In the present study, a rat model of PAH induced by 5 weeks of chronic hypoxia and treatment with a single injection of monocrotaline (60 mg/kg) was used to investigate the involvement of CXCR4 in PAH. Successful establishment of the PAH model was confirmed by significant differences between the PAH and control groups in right ventricular systolic pressure, Fulton index, wall thickness, vascular occlusion score determined by immunohistochemical staining and the expression of inflammatory markers measured by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The expression of CXCR4 and other stem cell markers were compared in the PAH and control groups. RT‑qPCR showed that the expression of CXCR4, SCF, c‑Kit, and CD29, which are expressed in MSCs, was significantly higher in the PAH group. Immunohistochemical staining also showed that the numbers of CXCR4‑, c‑Kit‑ and CD90‑positive cells were significantly higher in the PAH group. These results suggest that CXCR4 is involved in the pathogenesis of PAH and that stem cells may serve an important role in pulmonary vascular remodeling.

View Figures

View References

1	Zhou L, Chen Z, Vanderslice P, So SP, Ruan KH, Willerson JT and Dixon RA: Endothelial-like progenitor cells engineered to produce prostacyclin rescue monocrotaline-induced pulmonary arterial hypertension and provide right ventricle benefits. Circulation. 128:982–994. 2013. View Article : Google Scholar : PubMed/NCBI
2	Cheng GS, Zhang YS, Zhang TT, He L and Wang XY: Bone marrow-derived mesenchymal stem cells modified with IGFBP-3 inhibit the proliferation of pulmonary artery smooth muscle cells. Int J Mol Med. 39:223–230. 2017. View Article : Google Scholar : PubMed/NCBI
3	Farber HW and Loscalzo J: Pulmonary arterial hypertension. N Engl J Med. 351:1655–1665. 2004. View Article : Google Scholar : PubMed/NCBI
4	Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmüller P, Guignabert C and Humbert M: Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: A complex interplay. Circulation. 129:1332–1340. 2014. View Article : Google Scholar : PubMed/NCBI
5	Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR and Morrell NW: Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 62 25 Suppl:D4–D12. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Péchoux C, Bogaard HJ, Dorfmüller P, Remy S, Lecerf F, Planté S, et al: Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 131:1006–1018. 2015. View Article : Google Scholar : PubMed/NCBI
7	Yang JX, Pan YY, Zhao YY and Wang XX: Endothelial progenitor cell-based therapy for pulmonary arterial hypertension. Cell Transplant. 22:1325–1336. 2013. View Article : Google Scholar : PubMed/NCBI
8	Chen H, Strappe P, Chen S and Wang LX: Endothelial progenitor cells and pulmonary arterial hypertension. Heart Lung Circ. 23:595–601. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, Zhu JH and Chen JZ: Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: A pilot randomized controlled trial. J Am Coll Cardiol. 49:1566–1571. 2007. View Article : Google Scholar : PubMed/NCBI
10	Lan B, Hayama E, Kawaguchi N, Furutani Y and Nakanishi T: Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension. PLoS One. 10:e01172112015. View Article : Google Scholar : PubMed/NCBI
11	Teicher BA and Fricker SP: CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 16:2927–2931. 2010. View Article : Google Scholar : PubMed/NCBI
12	Miller RJ, Banisadr G and Bhattacharyya BJ: CXCR4 signaling in the regulation of stem cell migration and development. J Neuroimmunol. 198:31–38. 2008. View Article : Google Scholar : PubMed/NCBI
13	Peng SB, Zhang X, Paul D, Kays LM, Gough W, Stewart J, Uhlik MT, Chen Q, Hui YH, Zamek-Gliszczynski MJ, et al: Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. Mol Cancer Ther. 14:480–490. 2015. View Article : Google Scholar : PubMed/NCBI
14	Farkas D, Kraskauskas D, Drake JI, Alhussaini AA, Kraskauskiene V, Bogaard HJ, Cool CD, Voelkel NF and Farkas L: CXCR4 inhibition ameliorates severe obliterative pulmonary hypertension and accumulation of C-kit⁺ cells in rats. PLoS One. 9:e898102014. View Article : Google Scholar : PubMed/NCBI
15	Morimatsu Y, Sakashita N, Komohara Y, Ohnishi K, Masuda H, Dahan D, Takeya M, Guibert C and Marthan R: Development and characterization of an animal model of severe pulmonary arterial hypertension. J Vasc Res. 49:33–42. 2012. View Article : Google Scholar : PubMed/NCBI
16	Rondelet B, Kerbaul F, Motte S, van Beneden R, Remmelink M, Brimioulle S, McEntee K, Wauthy P, Salmon I, Ketelslegers JM and Naeije R: Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation. 107:1329–1335. 2003. View Article : Google Scholar : PubMed/NCBI
17	Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, Qiu D, Benson G, Pearl RG and Kao PN: Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation. 108:1640–1645. 2003. View Article : Google Scholar : PubMed/NCBI
18	Bahmanpour S, Khozani Talaei T, Fard Zarei N, Jaberipour M, Hosseini A and Esmaeilpour T: A comparison of the multiple oocyte maturation gene expression patterns between the newborn and adult mouse ovary. Iran J Reprod Med. 11:815–822. 2013.PubMed/NCBI
19	Stenmark KR, Meyrick B, Galie N, Mooi WJ and McMurtry IF: Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol. 297:L1013–L1032. 2009. View Article : Google Scholar : PubMed/NCBI
20	Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA and Botney MD: Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol. 151:1019–1025. 1997.PubMed/NCBI
21	Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF and Oka M: Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation. 121:2747–2754. 2010. View Article : Google Scholar : PubMed/NCBI
22	Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogórek B, Rondon-Clavo C, Ferreira-Martins J, et al: Evidence for human lung stem cells. N Engl J Med. 364:1795–1806. 2011. View Article : Google Scholar : PubMed/NCBI
23	Fang S, Wei J, Pentinmikko N, Leinonen H and Salven P: Generation of functional blood vessels from a single c-kit+ adult vascular endothelial stem cell. PLoS Biol. 10:e10014072012. View Article : Google Scholar : PubMed/NCBI
24	Kim JY, Choi JS, Song SH, Im JE, Kim JM, Kim K, Kwon S, Shin HK, Joo CK, Lee BH and Suh W: Stem cell factor is a potent endothelial permeability factor. Arterioscler Thromb Vasc Biol. 34:1459–1467. 2014. View Article : Google Scholar : PubMed/NCBI
25	Ridzuan N, Al Abbar A, Yip WK, Maqbool M and Ramasamy R: Characterization and expression of senescence marker in prolonged passages of rat bone marrow-derived mesenchymal stem cells. Stem Cells Int. 2016:84872642016. View Article : Google Scholar : PubMed/NCBI
26	Huang X, Wu P, Huang F, Xu M, Chen M, Huang K, Li GP, Xu M, Yao D and Wang L: Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling. J Biomed Sci. 24:522017. View Article : Google Scholar : PubMed/NCBI
27	Favre S, Gambini E, Nigro P, Scopece A, Bianciardi P, Caretti A, Pompilio G, Corno AF, Vassalli G, von Segesser LK, et al: Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells. J Cell Mol Med. 21:871–880. 2017. View Article : Google Scholar : PubMed/NCBI
28	Young KC, Torres E, Hatzistergos KE, Hehre D, Suguihara C and Hare JM: Inhibition of the SDF-1/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension. Circ Res. 104:1293–1301. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ling X, Spaeth E, Chen Y, Shi Y, Zhang W, Schober W, Hail N Jr, Konopleva M and Andreeff M: The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo. PLoS One. 8:e584262013. View Article : Google Scholar : PubMed/NCBI
30	Galsky MD, Vogelzang NJ, Conkling P, Raddad E, Polzer J, Roberson S, Stille JR, Saleh M and Thornton D: A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer. Clin Cancer Res. 20:3581–3588. 2014. View Article : Google Scholar : PubMed/NCBI
31	Arakaki R, Tamamura H, Premanathan M, Kanbara K, Ramanan S, Mochizuki K, Baba M, Fujii N and Nakashima H: T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure. J Virol. 73:1719–1723. 1999.PubMed/NCBI
32	Yang JX, Zhang N, Wang HW, Gao P, Yang QP and Wen QP: CXCR4 receptor overexpression in mesenchymal stem cells facilitates treatment of acute lung injury in rats. J Biol Chem. 290:1994–2006. 2015. View Article : Google Scholar : PubMed/NCBI