Endothelial Unc5B controls blood-brain barrier integrity

Abstract

Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/β-catenin signaling, and β-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases.

Historical and current perspectives on blood endothelial cell heterogeneity in the brain

“…The key components of Wnt7s/β-catenin signaling are the receptor complexes consisting of Frizzled, Lrps, Gpr124, and Reck [ 138 , 141 – 144 ], while Norrin/β-catenin signaling requires Frizzled-4 [ 145 , 146 ] and another co-receptor component called Tspan12 [ 140 , 147 ]. A recent study has reported that the guidance cue Netrin-1 signaling through its Unc5B receptor is critical for activating endothelial β-catenin pathways to maintain BBB integrity in mice [ 148 ].…”

“…Emerging therapeutic targets include the Netrin1-Unc5B signaling axis that is indicated to act upstream of canonical β-catenin pathways in the brain [ 148 ]. Current evidence shows that Netrin-1 global knockouts [ 262 ] or endothelial-specific deletion of the Unc5B receptor in mice [ 148 ] led to the down-regulation of BBB markers in vECs, while upregulating their PLVAP expression [ 148 ].…”

“…Emerging therapeutic targets include the Netrin1-Unc5B signaling axis that is indicated to act upstream of canonical β-catenin pathways in the brain [ 148 ]. Current evidence shows that Netrin-1 global knockouts [ 262 ] or endothelial-specific deletion of the Unc5B receptor in mice [ 148 ] led to the down-regulation of BBB markers in vECs, while upregulating their PLVAP expression [ 148 ]. In contrast, Netrin-1 treatments can enhance BBB marker expression both in vitro and in vivo [ 148 , 192 , 262 ] and reduce BBB leakage in mouse models of MS [ 262 ] and BBB breakdown [ 192 ], suggesting BBB protective effects of Netrin-1-Unc5B signaling.…”

“…In many pathological and developmental conditions where endothelial BBB integrity and identities are disrupted, upregulation of PLVAP expression in vECs has been reported. For example, PLVAP upregulation is detected in microvasculature associated with brain tumors and ischemia [ 263 – 265 ] where neuroinflammation and BBB breakdown occur, or in vasculature where reduced levels of endothelial β-catenin signaling are observed [ 114 , 138 , 140 , 148 ]. These observations are consistent with the current model that active β-catenin signaling suppresses PLVAP expression in brain vECs to establish the BBB [ 29 , 30 , 114 ].…”

Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders

“…It has been recently proved that the blocking the binding of Netrin-1 with Unc5B and delivery of monoclonal antibodies prompts the opening of BBB for various molecules transiently. This would pave way for delivery of therapeutics for various neurological disorders [ 250 ]. Wnt 7a and 7b are the signals that induce the formation of the BBB and are also involved in BBB repair.…”