Endothelial Nitric Oxide Synthase–Deficient Mice
2021; Elsevier BV; Volume: 191; Issue: 11 Linguagem: Inglês
10.1016/j.ajpath.2021.02.022
ISSN1525-2191
AutoresFrancesca‐Fang Liao, Geng Lin, Xingyong Chen, Ling Chen, Wei Xing Zheng, Rajendra Raghow, Fu-Ming Zhou, Andy Y. Shih, Xing-Lin Tan,
Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoAge-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)–deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation. Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)–deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation. Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer disease (AD).1Snyder H.M. Corriveau R.A. Craft S. Faber J.E. Greenberg S. Knopman D. Lamb B.T. Montine T. Nedergaard M. Schaffer C.B. Schneider J.A. Wellington C. Wilcock D.M. Zipfel G.J. Zlokovic B. Bain L.J. Bosetti F. Galis Z.S. Koroshetz W. 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Fortuitously, over the years, these conceptual hurdles have been steadily mitigated with the generation of transgenic mice engineered with deletions of functional NOS1, NOS2, or NOS3 genes from their genomes, which encode nNOS, iNOS, and eNOS, respectively. Detailed analyses of several lines of such transgenic mice unraveled not only how the lack of a particular NOS isozyme affects the basal phenotype of the mice but also their responses to varied experimental manipulations.41Liu V.W.T. Huang P.L. Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice.Cardiovasc Res. 2008; 77: 19-29PubMed Google Scholar eNOS-deficient mice were generated by three independent laboratories.42Shesely E.G. Maeda N. Kim H.S. Desai K.M. Krege J.H. Laubach V.E. Sherman P.A. Sessa W.C. Smithies O. 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