Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

Abstract

Neurogenesis and angiogenesis play important roles in functional recovery after ischemic stroke. When cerebral ischemia occurs, axon regeneration can compensate for the loss of apoptotic neurons in the ischemic area. The formation of new blood vessels ameliorates the local decrease in blood supply, enhancing the supply of oxygen and nutrients to newly-formed neurons. New blood vessels also act as a scaffold for the migration of neuroblasts to the infarct area after ischemic stroke. In light of this, researchers have been actively searching for methods to treat cerebral infarction. Netrins were fi rst identifi ed as a family of proteins that mediate axon guidance and direct axon migration during embryogenesis. Later studies have revealed other functions of this protein family. In this review, we focus on netrin-1, which has been shown to be involved in axon migration and angiogenesis, which are required for recovery after cerebral ischemia. Thus, therapies targeting netrin-1 may be useful for the treatment of ischemic stroke.

Netrin‐1 overexpression improves neurobehavioral outcomes and reduces infarct size via inhibition of the notch1 pathway following experimental stroke

“…The results of this study demonstrated the neuroprotective effects of Netrin‐1 against infarct‐induced brain injury. Netrin‐1 is an axonal guidance protein (Ding et al, ; Ylivinkka et al, ) that has been shown to have neuroprotective effects following cerebral infarction (Wu et al, ; Ding et al, ; Cirulli et al, ). Our results suggest that this effect is exerted via inhibition of the Notch1 pathway, which is consistent with the reported neuroprotective effects of Notch1 signaling (Arumugam et al, ; Wang et al, ).…”

“…The administration of Netrin‐1 has been shown to suppress ischemia‐induced neuronal apoptosis at sites of cerebral infarction (Wu et al, ; Liao S et al, ), promote remyelination and oligodendrocyte differentiation (He et al, ), and improve motor activity and exploratory behavior (Sun et al, ; Lu et al, ; Lu et al, 2012). It has also been shown to increase vascular density and stimulate the migration of neurons to the infarct region (Sun et al, ; Lu et al, 2012; Chen et al, ; Ding et al, ). A mechanism by which Netrin‐1 suppresses mesenchymal cell apoptosis has been proposed (Son et al, ); however, it is unclear whether a similar process occurs in the brain.…”

Microarray Profiling and Co-Expression Network Analysis of LncRNAs and mRNAs in Neonatal Rats Following Hypoxic-ischemic Brain Damage

“…This particular group included 6 genes, DCC, MET, NRP1, PAK3, PAK6, and UNC5B, all of which exhibited decreased expression. DCC (deleted in colorectal cancer) and UNC5B are two main receptors for netrins 29 . Netrins are a family of proteins that mediate axon guidance and direct axon migration during embryogenesis 29 and can promote the recovery of neuronal function after cerebral ischemia 30 31 32 .…”

Tumor angiogenesis revisited: Regulators and clinical implications

“…Although the netrins were the first axon guidance molecules to be identified, the role of netrin 1 and netrin 4 in angiogenesis has yet to be understood since contradictory results have been obtained in vitro and in vivo . Besides, expression of netrin 1, the most studied netrin, has only been demonstrated in few tumors, although its receptor UNC5B is strongly expressed in tumor blood vessels …”