Overexpression of netrin-1 induces neovascularization in the adult mouse brain.
Netrin-1 is a critical molecule for axonal pathfinding during embryo development, and because of its structural homology to the endothelial mitogens, it may share its effects on vascular network formation. Using an adeno-associated viral netrin-1 vector (AAV-NT-1) gene transfer, we demonstrated that netrin-1 was able to stimulate the proliferation and migration of human cerebral endothelial cells (HCECs) and human aortic smooth muscle cells (HASMCs) compared with the control (P<0.05), and could also promote HCEC tube formation on matrigel (P<0.05) in vitro. Moreover, netrin-1 hyperstimulation could promote focal neovascularization (P<0.05) in the adult brain in vivo. Unlike VEGF-induced microvessel increase, netrin-1-induced newly formed vessels showed an artery-like phenotype, with an intact endothelial cell monolayer surrounded by multiple cell layers, including smooth muscle cells and an astrocyte-connected outer layer. Our findings suggest that netrin-1 plays an important role in promoting blood vessel formation in the adult rodent central nervous system, and could have broad implication in cerebrovascular development and remodeling.
Fan
Yongfeng
Y
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94110, USA.
Shen
Fanxia
F
Chen
Yongmei
Y
Hao
Qi
Q
Liu
Weizhong
W
Su
Hua
H
Young
William L
WL
Yang
Guo-Yuan
GY
D000818:Animals; D001921:Brain / Q000098:blood supply*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002531:Cerebellum / Q000098:blood supply / Q000166:cytology; D002645:Chickens; D042783:Endothelial Cells; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075388:Netrin-1; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1