Nogo-A regulates vascular network architecture in the postnatal brain

Abstract

Recently, we discovered a new role for the well-known axonal growth inhibitory molecule Nogo-A as a negative regulator of angiogenesis in the developing central nervous system. However, how Nogo-A affected the three-dimensional (3D) central nervous system (CNS) vascular network architecture remained unknown. Here, using vascular corrosion casting, hierarchical, synchrotron radiation mCT-based network imaging and computer-aided network analysis, we found that genetic ablation of Nogo-A significantly increased the three-dimensional vascular volume fraction in the postnatal day 10 (P10) mouse brain. More detailed analysis of the cerebral cortex revealed that this effect was mainly due to an increased number of capillaries and capillary branchpoints. Interestingly, other vascular parameters such as vessel diameter, -length, -tortuosity, and -volume were comparable between both genotypes for non-capillary vessels and capillaries. Taken together, our three-dimensional data showing more vessel segments and branchpoints at unchanged vessel morphology suggest that stimulated angiogenesis upon Nogo-A gene deletion results in the insertion of complete capillary micro-networks and not just single vessels into existing vascular networks. These findings significantly enhance our understanding of how angiogenesis, vascular remodeling, and three-dimensional vessel network architecture are regulated during central nervous system development. Nogo-A may therefore be a potential novel target for angiogenesis-dependent central nervous system pathologies such as brain tumors or stroke.

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

“…Or conversely, there might be fewer anti-angiogenic molecules in visual cortex. Molecules such as Nogo-A and Angiopoietin-1 are known to be important negative regulators of vascular remodeling and angiogenesis (Lacoste and Gu, 2015;Wälchli et al, 2017). Whether these proteins are expressed in a regional gradient is unknown.…”

White-matter repair: Interaction between oligodendrocytes and the neurovascular unit

“…[ 38 ] Nogo signaling pathways in the brains of postnatal mice, in which blood vessels are still developing, exhibit how oligodendrocytes can also inhibit angiogenesis through negative regulation. [ 39 40 ] Blood vessels increase when Nogo-A is reduced via gene knockout, inhibition by an antibody, or knockdown induced by a virus. Moreover, adding the antibody to Nogo-A nullifies Nogo-A-mediated obstruction of brain microvascular endothelial cell migration.…”

Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain

“…The INVP is expanded and refined via subsequent vessel sprouting, branching and anastomosis 6,31,36,37 while these vascular sprouts migrate from the PNVP radially inwards towards the ventricles 3,27,36 . These important angiogenic processes of blood vessel formation and remodeling start during embryonic CNS development 31,36 and continue at the postnatal stage of brain development 17,27,30,38–40 . The expansion and remodeling of the intricate 3D CNS vascular network 38,39 is required in order to adapt to local metabolic needs and neural activity 27,38,39,41 .…”