Critical role of platelet-derived growth factor–α in angiogenesis after indirect bypass in a murine moyamoya disease model

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  • 1 Departments of Neurosurgery,
  • 2 Pathology, and
  • 3 Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
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OBJECTIVE

This study aimed to clarify the underlying mechanism of pathognomonic angiogenesis between the temporal muscle and neocortex after indirect bypass for moyamoya disease by shedding light on the role of platelet-derived growth factor receptor–α (PDGFRα) in angiogenesis.

METHODS

The gene for PDGFRα was systemically inactivated in adult mice (α-KO mice). The Pdgfra-preserving mice (Flox mice) and α-KO mice were exposed to bilateral common carotid artery stenosis (BCAS) by using microcoils. One week later the animals underwent encephalomyosynangiosis (EMS) on the right side. Cerebral blood flow (CBF) was serially measured using a laser Doppler flowmeter. Histological analysis was performed on the distribution of CD31-positive vessels and collagen deposit at 28 days after BCAS. Reverse transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of collagen mRNA in the skin fibroblasts derived from Flox and α-KO mice.

RESULTS

BCAS significantly reduced CBF up to approximately 70% of the control level at 28 days after the onset. There was no significant difference in CBF between Flox and α-KO mice. EMS significantly enhanced the improvement of CBF on the ipsilateral side of Flox mice, but not α-KO mice. EMS significantly induced the development of CD31-positive vessels in both the neocortex and temporal muscle on the ipsilateral side of Flox mice, but not α-KO mice. Deposition of collagen was distinctly observed between them in Flox mice, but not α-KO mice. Expression of mRNA of collagen type 1 alpha 1 (Col1a1) and collagen type 3 alpha 1 (Col3a1) was significantly downregulated in the skin fibroblasts from α-KO mice.

CONCLUSIONS

This is the first study that denotes the role of a specific growth factor in angiogenesis after EMS for moyamoya disease by inactivating its gene in mice. The findings strongly suggest that PDGFRα signal may play an important role in developing spontaneous angiogenesis between the temporal muscle and neocortex after EMS in moyamoya disease.

ABBREVIATIONS BCAS = bilateral common carotid artery stenosis; CBF = cerebral blood flow; CCA = common carotid artery; ECM = extracellular matrix; EMS = encephalomyosynangiosis; ICA = internal carotid artery; PCR = polymerase chain reaction; PDGF = platelet-derived growth factor; PDGFR = PDGF receptor; RT-PCR = reverse transcription PCR.

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Contributor Notes

Correspondence Satoshi Kuroda: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. skuroda@med.u-toyama.ac.jp.

INCLUDE WHEN CITING Published online May 22, 2020; DOI: 10.3171/2020.3.JNS193273.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7(11):10561066.

  • 2

    Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20(3):288299.

    • Search Google Scholar
    • Export Citation
  • 3

    Arikan F, Vilalta J, Torne R, Rapid resolution of brain ischemic hypoxia after cerebral revascularization in moyamoya disease. Neurosurgery. 2015;76(3):302312.

    • Search Google Scholar
    • Export Citation
  • 4

    Hecht N, Marushima A, Nieminen M, Myoblast-mediated gene therapy improves functional collateralization in chronic cerebral hypoperfusion. Stroke. 2015;46(1):203211.

    • Search Google Scholar
    • Export Citation
  • 5

    Hecht N, Peña-Tapia P, Vinci M, Myoblast-mediated gene therapy via encephalomyosynangiosis—a novel strategy for local delivery of gene products to the brain surface. J Neurosci Methods. 2011;201(1):6166.

    • Search Google Scholar
    • Export Citation
  • 6

    Hiramatsu M, Hishikawa T, Tokunaga K, Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. J Neurosurg. 2017;127(3):679686.

    • Search Google Scholar
    • Export Citation
  • 7

    Nakamura M, Imai H, Konno K, Experimental investigation of encephalomyosynangiosis using gyrencephalic brain of the miniature pig: histopathological evaluation of dynamic reconstruction of vessels for functional anastomosis. Laboratory investigation. J Neurosurg Pediatr. 2009;3(6):488495.

    • Search Google Scholar
    • Export Citation
  • 8

    Ohmori Y, Morioka M, Kaku Y, Granulocyte colony-stimulating factor enhances the angiogenetic effect of indirect bypass surgery for chronic cerebral hypoperfusion in a rat model. Neurosurgery. 2011;68(5):13721379.

    • Search Google Scholar
    • Export Citation
  • 9

    Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35(11):25982603.

    • Search Google Scholar
    • Export Citation
  • 10

    Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22(10):12761312.

    • Search Google Scholar
    • Export Citation
  • 11

    Ðặng TC, Ishii Y, Nguyen V, Powerful homeostatic control of oligodendroglial lineage by PDGFRα in adult brain. Cell Rep. 2019;27(4):10731089.e5.

    • Search Google Scholar
    • Export Citation
  • 12

    Olson LE, Soriano P. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell. 2009;16(2):303313.

    • Search Google Scholar
    • Export Citation
  • 13

    Horikawa S, Ishii Y, Hamashima T, PDGFRα plays a crucial role in connective tissue remodeling. Sci Rep. 2015;5:17948.

  • 14

    Lim M, Cheshier S, Steinberg GK. New vessel formation in the central nervous system during tumor growth, vascular malformations, and moyamoya. Curr Neurovasc Res. 2006;3(3):237245.

    • Search Google Scholar
    • Export Citation
  • 15

    Kusaka N, Sugiu K, Tokunaga K, Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery. J Neurosurg. 2005;103(5):882890.

    • Search Google Scholar
    • Export Citation
  • 16

    Kim HS, Lee HJ, Yeu IS, The neovascularization effect of bone marrow stromal cells in temporal muscle after encephalomyosynangiosis in chronic cerebral ischemic rats. J Korean Neurosurg Soc. 2008;44(4):249255.

    • Search Google Scholar
    • Export Citation
  • 17

    Hokari M, Kuroda S, Iwasaki Y. Pretreatment with the ciclosporin derivative NIM811 reduces delayed neuronal death in the hippocampus after transient forebrain ischaemia. J Pharm Pharmacol. 2010;62(4):485490.

    • Search Google Scholar
    • Export Citation
  • 18

    Marushima A, Nieminen M, Kremenetskaia I, Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia. J Cereb Blood Flow Metab. 2020;40(2):404419.

    • Search Google Scholar
    • Export Citation
  • 19

    Ulrich PT, Kroppenstedt S, Heimann A, Kempski O. Laser-Doppler scanning of local cerebral blood flow and reserve capacity and testing of motor and memory functions in a chronic 2-vessel occlusion model in rats. Stroke. 1998;29(11):24122420.

    • Search Google Scholar
    • Export Citation
  • 20

    Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986;261(9):43374345.

    • Search Google Scholar
    • Export Citation
  • 21

    Oberringer M, Meins C, Bubel M, Pohlemann T. In vitro wounding: effects of hypoxia and transforming growth factor beta1 on proliferation, migration and myofibroblastic differentiation in an endothelial cell-fibroblast co-culture model. J Mol Histol. 2008;39(1):3747.

    • Search Google Scholar
    • Export Citation
  • 22

    Hurskainen M, Eklund L, Hägg PO, Abnormal maturation of the retinal vasculature in type XVIII collagen/endostatin deficient mice and changes in retinal glial cells due to lack of collagen types XV and XVIII. FASEB J. 2005;19(11):15641566.

    • Search Google Scholar
    • Export Citation
  • 23

    Sottile J. Regulation of angiogenesis by extracellular matrix. Biochim Biophys Acta. 2004;1654(1):1322.

  • 24

    Aoyagi M, Fukai N, Matsushima Y, Kinetics of 125I-PDGF binding and down-regulation of PDGF receptor in arterial smooth muscle cells derived from patients with moyamoya disease. J Cell Physiol. 1993;154(2):281288.

    • Search Google Scholar
    • Export Citation
  • 25

    Aoyagi M, Fukai N, Yamamoto M, Development of intimal thickening in superficial temporal arteries in patients with moyamoya disease. Clin Neurol Neurosurg. 1997;99(suppl 2):S213S217.

    • Search Google Scholar
    • Export Citation
  • 26

    Kang HS, Kim JH, Phi JH, Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81(6):673678.

    • Search Google Scholar
    • Export Citation
  • 27

    Schneider CA, Rasband WS, Eliceiri KW. NIH image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671675.

  • 28

    Abramoff MD, Magelhaes PJ, Ram SJ. Image processing with ImageJ. Biophotonics Int. 2004;11:3642.

  • 29

    Yamamoto S, Niida S, Azuma E, Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. Sci Rep. 2015;5:8505.

    • Search Google Scholar
    • Export Citation

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