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Neurotherapeutics

, Volume 16, Issue 3, pp 901–911 | Cite as

Increased TRPM4 Activity in Cerebral Artery Myocytes Contributes to Cerebral Blood Flow Reduction After Subarachnoid Hemorrhage in Rats

  • Yi Gong
  • Ming-yue Du
  • Hua-lin Yu
  • Zhi-yong Yang
  • Yu-jin Li
  • Lei Zhou
  • Rong Mei
  • Li Yang
  • Fei WangEmail author
Original Article

Abstract

Cerebral blood flow (CBF) reduction underlies unfavorable outcomes after subarachnoid hemorrhage (SAH). Transient receptor potential melastatin-4 (TRPM4) has a pivotal role in cerebral artery myogenic tone maintenance and CBF regulation under physiological conditions. However, the role of TRPM4 in CBF reduction after SAH is unclear. In this study, we aimed at testing whether TRPM4 would contribute to CBF reduction after SAH in vivo and determining underlying mechanisms. Rat SAH model was established by stereotaxic injection of autologous nonheparinized arterial blood at the suprasellar cistern. A TRPM4 blocker, 9-phenanthrol (9-Phe), was infused through an intraventricular catheter connected to a programmed subcutaneous pump to evaluate the contribution of TRPM4 to SAH outcomes. TRPM4 expression and translocation in cerebral artery myocytes were detected by immunoblotting. Macroscopic currents in cerebral artery myocytes were determined by whole-cell patch clamp. Myogenic tone of cerebral arteries was studied by pressurized myography. Cortical and global CBFs were measured via laser Doppler flowmetry and fluorescent microspheres, respectively. After SAH, TRPM4 translocation and macroscopic current density increased significantly. Furthermore, TRPM4 accounted for a greater proportion of myogenic tone after SAH, suggesting an upregulation of TRPM4 activity in response to SAH. Cortical and global CBFs were reduced after SAH, but were restored significantly by 9-Phe, implying that TRPM4 contributed to CBF reduction after SAH. Collectively, these discoveries show that increased TRPM4 activity has a pivotal role in CBF reduction after SAH, and provide a novel target for the management of cerebral perfusion dysfunction following SAH.

Key Words

Subarachnoid hemorrhage transient receptor potential melastatin-4 myogenic tone cerebral vasospasm cerebral blood flow. 

Notes

Acknowledgments

The authors thank Dr. Siu-Lung Chan for critically review and intellectual input on this manuscript. This work was supported by the National Natural Science Foundation of China (Nos. 81760223, 81560206), Natural Science Foundation of Yunnan Province (Nos. FB2016121, 2014FB087), Yunnan Health Training Project in High Level Talents (No. H-201601), Technology and Science Innovation Team Foundation of Kunming Medical University (No. CXTD201707), Yunnan Key Laboratory of Medicine Funding (No. 2017DG005), and Internal Funding of Yunnan Provincial Health and Family Planning Commission (No. 2016NS205).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2019_741_MOESM1_ESM.docx (56 kb)
ESM 1 (DOCX 55 kb)
13311_2019_741_MOESM2_ESM.docx (29 kb)
ESM 2 (DOCX 28 kb)
13311_2019_741_MOESM3_ESM.pdf (490 kb)
ESM 3 (PDF 490 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Yi Gong
    • 1
    • 2
    • 3
  • Ming-yue Du
    • 1
  • Hua-lin Yu
    • 1
  • Zhi-yong Yang
    • 1
  • Yu-jin Li
    • 4
  • Lei Zhou
    • 5
  • Rong Mei
    • 6
  • Li Yang
    • 7
  • Fei Wang
    • 1
    • 2
    Email author
  1. 1.Department of NeurosurgeryThe First Affiliated Hospital of Kunming Medical UniversityKunmingChina
  2. 2.Yunnan Key Laboratory of Laboratory MedicineKunmingChina
  3. 3.Department of NeurosurgeryThe Third People’s Hospital of Yunnan ProvinceKunmingChina
  4. 4.Department of AnesthesiologyThe First People’s Hospital of Yunnan ProvinceKunmingChina
  5. 5.The Key Laboratory of Stem Cell and Regenerative Medicine of Yunnan Province, Institute of Molecular and Clinical MedicineKunming Medical UniversityKunmingChina
  6. 6.Department of NeurologyThe First People’s Hospital of Yunnan ProvinceKunmingChina
  7. 7.Department of Anatomy, Histology and EmbryologyKunming Medical UniversityKunmingChina

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