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- Title
Astrocytic neogenin/netrin-1 pathway promotes blood vessel homeostasis and function in mouse cortex.
- Authors
Ling-Ling Yao; Jin-Xia Hu; Qiang Li; Daehoon Lee; Xiao Ren; Jun-Shi Zhang; Dong Sun; Hong-Sheng Zhang; Yong-Gang Wang; Lin Mei; Wen-Cheng Xiong; Yao, Ling-Ling; Hu, Jin-Xia; Li, Qiang; Lee, Daehoon; Ren, Xiao; Zhang, Jun-Shi; Sun, Dong; Zhang, Hong-Sheng; Wang, Yong-Gang
- Abstract
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.
- Subjects
BLOOD vessels; COLON cancer; HOMEOSTASIS; FUNCTIONS of bounded variation; BASAL lamina
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p6490
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI132372