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Astrocytic neogenin/netrin-1 pathway promotes blood vessel homeostasis and function in mouse cortex.
Yao, Ling-Ling; Hu, Jin-Xia; Li, Qiang; Lee, Daehoon; Ren, Xiao; Zhang, Jun-Shi; Sun, Dong; Zhang, Hong-Sheng; Wang, Yong-Gang; Mei, Lin; Xiong, Wen-Cheng.
Affiliation
  • Yao LL; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Hu JX; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Li Q; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Lee D; Institute of Stroke Center and Department of Neurology, Xuzhou Medical University, The Affiliated Hospital of Xuzhou Medical University, Jiangsu, China.
  • Ren X; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Zhang JS; Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, China.
  • Sun D; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Zhang HS; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Wang YG; Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • Mei L; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Xiong WC; Department of Neurology, Huaihe Hospital, Henan University, Kaifeng, Henan, China.
J Clin Invest ; 130(12): 6490-6509, 2020 12 01.
Article in En | MEDLINE | ID: mdl-32853179
Astrocytes have multiple functions in the brain, including affecting blood vessel (BV) homeostasis and function. However, the underlying mechanisms remain elusive. Here, we provide evidence that astrocytic neogenin (NEO1), a member of deleted in colorectal cancer (DCC) family netrin receptors, is involved in blood vessel homeostasis and function. Mice with Neo1 depletion in astrocytes exhibited clustered astrocyte distribution and increased BVs in their cortices. These BVs were leaky, with reduced blood flow, disrupted vascular basement membranes (vBMs), decreased pericytes, impaired endothelial cell (EC) barrier, and elevated tip EC proliferation. Increased proliferation was also detected in cultured ECs exposed to the conditioned medium (CM) of NEO1-depleted astrocytes. Further screening for angiogenetic factors in the CM identified netrin-1 (NTN1), whose expression was decreased in NEO1-depleted cortical astrocytes. Adding NTN1 into the CM of NEO1-depleted astrocytes attenuated EC proliferation. Expressing NTN1 in NEO1 mutant cortical astrocytes ameliorated phenotypes in blood-brain barrier (BBB), EC, and astrocyte distribution. NTN1 depletion in astrocytes resulted in BV/BBB deficits in the cortex similar to those in Neo1 mutant mice. In aggregate, these results uncovered an unrecognized pathway, astrocytic NEO1 to NTN1, not only regulating astrocyte distribution, but also promoting cortical BV homeostasis and function.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cerebral Cortex / Astrocytes / Neovascularization, Physiologic / Netrin-1 / Homeostasis / Membrane Proteins Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Clin Invest Year: 2020 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cerebral Cortex / Astrocytes / Neovascularization, Physiologic / Netrin-1 / Homeostasis / Membrane Proteins Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Clin Invest Year: 2020 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos