• ISSN 1674-8301
  • CN 32-1810/R
Volume 36 Issue 5
Sep.  2022
Turn off MathJax
Article Contents
Xi Yan, Junkui Shang, Runrun Wang, Fengyu Wang, Jiewen Zhang. Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy[J]. The Journal of Biomedical Research, 2022, 36(5): 353-357. doi: 10.7555/JBR.36.20220208
Citation: Xi Yan, Junkui Shang, Runrun Wang, Fengyu Wang, Jiewen Zhang. Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy[J]. The Journal of Biomedical Research, 2022, 36(5): 353-357. doi: 10.7555/JBR.36.20220208

Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

doi: 10.7555/JBR.36.20220208
Funds:  This work was supported by National Natural Science Foundation of China (Grants No. 81873727 and 82171196).
More Information
  • Corresponding author: Jiewen Zhang, Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, No. 7 Weiwu Road, Zhengzhou, Henan 450003, China. Tel: +86-371-65580782, E-mail: zhangjiewen9900@126.com
  • Received: 2022-02-21
  • Revised: 2022-06-15
  • Accepted: 2022-07-07
  • Published: 2022-08-28
  • Issue Date: 2022-09-28
  • Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.


  • CLC number: R743, Document code: A
    The authors reported no conflict of interests.
  • loading
  • [1]
    Di Donato I, Bianchi S, De Stefano N, et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects[J]. BMC Med, 2017, 15(1): 41. doi: 10.1186/s12916-017-0778-8
    Schoemaker D, Quiroz YT, Torrico-Teave H, et al. Clinical and research applications of magnetic resonance imaging in the study of CADASIL[J]. Neurosci Lett, 2019, 698: 173–179. doi: 10.1016/j.neulet.2019.01.014
    Huneau C, Houot M, Joutel A, et al. Altered dynamics of neurovascular coupling in CADASIL[J]. Ann Clin Transl Neurol, 2018, 5(7): 788–802. doi: 10.1002/acn3.574
    Joutel A, Monet-Leprêtre M, Gosele C, et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease[J]. J Clin Invest, 2010, 120(2): 433–445. doi: 10.1172/JCI39733
    Mašek J, Andersson ER. The developmental biology of genetic Notch disorders[J]. Development, 2017, 144(10): 1743–1763. doi: 10.1242/dev.148007
    Liu H, Zhang W, Kennard S, et al. Notch3 is critical for proper angiogenesis and mural cell investment[J]. Circ Res, 2010, 107(7): 860–870. doi: 10.1161/CIRCRESAHA.110.218271
    Monet-Leprêtre M, Haddad I, Baron-Menguy C, et al. Abnormal recruitment of extracellular matrix proteins by excess Notch3ECD: a new pathomechanism in CADASIL[J]. Brain, 2013, 136(6): 1830–1845. doi: 10.1093/brain/awt092
    Zellner A, Scharrer E, Arzberger T, et al. CADASIL brain vessels show a HTRA1 loss-of-function profile[J]. Acta Neuropathol, 2018, 136(1): 111–125. doi: 10.1007/s00401-018-1853-8
    Fan D, Kassiri Z. Biology of tissue inhibitor of metalloproteinase 3 (TIMP3), and its therapeutic implications in cardiovascular pathology[J]. Front Physiol, 2020, 11: 661. doi: 10.3389/fphys.2020.00661
    Capone C, Cognat E, Ghezali L, et al. Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice[J]. Ann Neurol, 2016, 79(3): 387–403. doi: 10.1002/ana.24573
    Capone C, Dabertrand F, Baron-Menguy C, et al. Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics[J]. Elife, 2016, 5: e17536. doi: 10.7554/eLife.17536
    Hanemaaijer ES, Panahi M, Swaddiwudhipong N, et al. Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells[J]. Eur J Cell Biol, 2018, 97(8): 557–567. doi: 10.1016/j.ejcb.2018.10.001
    Neves KB, Morris HE, Alves-Lopes R, et al. Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of NO/sGC/cGMP pathway[J]. Clin Sci (Lond), 2021, 135(6): 753–773. doi: 10.1042/CS20201412
    Henshall TL, Keller A, He L, et al. Notch3 is necessary for blood vessel integrity in the central nervous system[J]. Arterioscler Thromb Vasc Biol, 2015, 35(2): 409–420. doi: 10.1161/ATVBAHA.114.304849
    Machuca-Parra AI, Bigger-Allen AA, Sanchez AV, et al. Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL[J]. J Exp Med, 2017, 214(8): 2271–2282. doi: 10.1084/jem.20161715
    Monet-Leprêtre M, Bardot B, Lemaire B, et al. Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain[J]. Brain, 2009, 132(6): 1601–1612. doi: 10.1093/brain/awp049
    Monet M, Domenga V, Lemaire B, et al. The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo[J]. Hum Mol Genet, 2007, 16(8): 982–992. doi: 10.1093/hmg/ddm042
    Baron-Menguy C, Domenga-Denier V, Ghezali L, et al. Increased Notch3 activity mediates pathological changes in structure of cerebral arteries[J]. Hypertension, 2017, 69(1): 60–70. doi: 10.1161/HYPERTENSIONAHA.116.08015
    Kisler K, Nelson AR, Montagne A, et al. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease[J]. Nat Rev Neurosci, 2017, 18(7): 419–434. doi: 10.1038/nrn.2017.48
    Brennan-Krohn T, Salloway S, Correia S, et al. Glial vascular degeneration in CADASIL[J]. J Alzheimers Dis, 2010, 21(4): 1393–1402. doi: 10.3233/JAD-2010-100036
    Hase Y, Chen A, Bates LL, et al. Severe white matter astrocytopathy in CADASIL[J]. Brain Pathol, 2018, 28(6): 832–843. doi: 10.1111/bpa.12621
    Mulligan SJ, MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions[J]. Nature, 2004, 431(7005): 195–199. doi: 10.1038/nature02827
    Takano T, Tian G, Peng W, et al. Astrocyte-mediated control of cerebral blood flow[J]. Nat Neurosci, 2006, 9(2): 260–267. doi: 10.1038/nn1623
    Jessen NA, Munk AS, Lundgaard I, et al. The glymphatic system: a beginner's guide[J]. Neurochem Res, 2015, 40(12): 2583–2599. doi: 10.1007/s11064-015-1581-6
    Benveniste H, Nedergaard M. Cerebral small vessel disease: a glymphopathy?[J]. Curr Opin Neurobiol, 2022, 72: 15–21. doi: 10.1016/j.conb.2021.07.006
    Koundal S, Elkin R, Nadeem S, et al. Optimal mass transport with lagrangian workflow reveals advective and diffusion driven solute transport in the glymphatic system[J]. Sci Rep, 2020, 10(1): 1990. doi: 10.1038/s41598-020-59045-9
    Jiang Q, Zhang L, Ding G, et al. Impairment of the glymphatic system after diabetes[J]. J Cereb Blood Flow Metab, 2017, 37(4): 1326–1337. doi: 10.1177/0271678X16654702
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (189) PDF downloads(25) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint