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Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension

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Abstract

Objectives

Pulmonary arterial hypertension (PAH) is a progressive disease which causes increased vascular resistance. In this study, our purpose was to quantify the micro-vascular remodeling in monocrotaline-induced PAH rats using synchrotron radiation pulmonary micro-angiography (SRPA), a method we have previously established in an in vivo rat model. To determine the relationship between endothelial function and vascular remodeling, the local expression of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) was evaluated using immunohistochemical staining.

Methods

Monocrotaline-induced PAH rats were created by subcutaneous injection of monocrotaline. After 2 weeks, SRPA was performed at the Photon Factory of the High Energy Accelerator Research Organization. The internal diameters of pulmonary arterioles were measured using SRPA images. Semi-quantified analyses of ET-1, eNOS and VEGF expression in pulmonary arterioles were performed by immunohistochemical staining.

Results

Micro-vascular density and the internal diameters of pulmonary arterioles were significantly decreased in PAH. ET-1 expression was significantly increased in PAH compared with the control (1.53 ± 0.45 vs. 0.80 ± 0.14) and eNOS expression was significantly decreased in PAH compared with the control (1.12 ± 0.59 vs. 1.91 ± 0.66), although VEGF expression did not differ between the groups.

Conclusions

SRPA can be effectively used for visualizing the decreased pulmonary micro-vasculature associated with PAH. Increased ET-1 expression and decreased eNOS expression may contribute to the proliferation and vasospasm of pulmonary arterioles induced by endothelial dysfunction due to PAH. This SRPA technology may help to identify a correlation between endothelial function and micro-vasculature remodeling in PAH.

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References

  1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425–36.

    Article  CAS  PubMed  Google Scholar 

  2. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.

  3. Matsushita S, Hyodo K, Imazuru T, Tokunaga C, Sato F, Enomoto Y, et al. The minimum coronary artery diameter in which coronary spasm can be identified by synchrotron radiation coronary angiography. Eur J Radiol. 2008;68:S84–8.

    Article  PubMed  Google Scholar 

  4. Sakamoto H, Matsushita S, Hyodo K, Tokunaga C, Sato F, Hiramatsu Y. A new technique of in vivo synchrotron radiation coronary microangiography in the rat. Acta Radiol. 2014;56:1105–7.

    Article  PubMed  Google Scholar 

  5. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res. 1993;73:887–97.

    Article  CAS  PubMed  Google Scholar 

  6. Miyauchi T, Sato R, Sakai S, Kobayashi T, Ueno M, Kondo H, et al. Endothelin-1 and right-sided heart failure in rats: effects of an endothelin receptor antagonist on the failing right ventricle. J Cardiovasc Pharmacol. 2000;36:S327–30.

    Article  CAS  PubMed  Google Scholar 

  7. Tokunaga CM, Hyodo S, Hiramatsu K, Sakakibara Y. Measurement of pulmonary arterial flow velocity, in a high flow pulmonary hypertension rat model using synchrotron radiation pulmonary micro-angiography. Circulation 2011;A11454.

  8. Ito H, Matsushita S, Hyodo K, Sato Y, Sakakibara Y. Using synchrotron radiation angiography with a highly sensitive detector to identify impaired peripheral perfusion in rat pulmonary emphysema. J Synchrotron Radiat. 2013;20:376–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Atkinson S, Fox SB. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol. 2004;203:721–8.

    Article  CAS  PubMed  Google Scholar 

  10. White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 2002;62:1669–75.

    CAS  PubMed  Google Scholar 

  11. Sato F, Matsushita S, Hyodo K, Akishima S, Imazuru T, Tokunaga C, et al. Sex difference in peripheral arterial response to cold exposure. Circ J. 2008;72:1367–72.

    Article  PubMed  Google Scholar 

  12. Yamaki S. Pulmonary vascular disease associated with pulmonary hypertension in 445 patients: diagnosis from lung biopsy and autopsy. Gen Thorac Cardiovasc Surg. 2013;61:24–31.

    Article  PubMed  Google Scholar 

  13. Aggarwal S, Gross CM, Sharma S, Fineman JR, Black SM. Reactive oxygen species in pulmonary vascular remodeling. Compr Physiol. 2013;3:1011–34.

    PubMed  PubMed Central  Google Scholar 

  14. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61:227–37.

    Article  CAS  PubMed  Google Scholar 

  15. Voelkel NF, Gomez-Arroyo J. The role of vascular endothelial growth factor in pulmonary arterial hypertension. The angiogenesis paradox. Am J Respir Cell Mol Biol. 2014;51:474–84.

    Article  PubMed  Google Scholar 

  16. Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195:367–74.

    Article  CAS  PubMed  Google Scholar 

  17. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation. 2010;121:2747–54.

    Article  PubMed  Google Scholar 

  18. Zamanian RT, Kudelko KT, Sung YK, de Jesus Perez V, Liu J, Spiekerkoetter E. Current clinical management of pulmonary arterial hypertension. Circ Res. 2014;115:131–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448–56.

    Article  PubMed  Google Scholar 

  20. Lau EM, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol. 2014;12:143–55.

    Article  PubMed  Google Scholar 

  21. Schwenke DO, Pearson JT, Kangawa K, Umetani K, Shirai M. Changes in macrovessel pulmonary blood flow distribution following chronic hypoxia: assessed using synchrotron radiation microangiography. J Appl Physiol. 1985;2008(104):88–96.

    Google Scholar 

  22. Shirai M, Beard M, Pearson JT, Sonobe T, Tsuchimochi H, Fujii Y, et al. Impaired pulmonary blood flow distribution in congestive heart failure assessed using synchrotron radiation microangiography. J Synchrotron Radiat. 2013;20:441–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 23791560.

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Authors and Affiliations

  1. School of Medicine, University of Tsukuba, Tsukuba, Japan

    Satoko Fuji

  2. Department of Cardiovascular Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan

    Motoo Osaka, Hiroaki Sakamoto, Yuji Hiramatsu & Chiho Tokunaga

  3. Department of Health Science, Tsukuba University of Technology, Tsukuba, Japan

    Shonosuke Matsushita

  4. Photon Factory, High Energy Accelerator Research Organization, Tsukuba, Japan

    Kazuyuki Hyodo

  5. Tokyo Denki University, Tsukuba, Japan

    Kenkichi Tanioka

  6. NHK Science and Technology Research Laboratories, Tsukuba, Japan

    Kazunori Miyakawa & Misao Kubota

Authors
  1. Satoko Fuji
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  2. Shonosuke Matsushita
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  3. Kazuyuki Hyodo
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  4. Motoo Osaka
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  5. Hiroaki Sakamoto
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  6. Kenkichi Tanioka
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  7. Kazunori Miyakawa
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  8. Misao Kubota
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  9. Yuji Hiramatsu
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  10. Chiho Tokunaga
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Corresponding author

Correspondence to Chiho Tokunaga.

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The authors have declared that no conflict of interest exists.

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Fuji, S., Matsushita, S., Hyodo, K. et al. Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension. Gen Thorac Cardiovasc Surg 64, 597–603 (2016). https://doi.org/10.1007/s11748-016-0684-6

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  • DOI: https://doi.org/10.1007/s11748-016-0684-6

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