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Cerebral angiogenesis ameliorates pathological disorders in Nemo-deficient mice with small-vessel disease

Item Type:Article
Title:Cerebral angiogenesis ameliorates pathological disorders in Nemo-deficient mice with small-vessel disease
Creators Name:Jiang, Y. and Müller, K. and Khan, M.A. and Assmann, J.C. and Lampe, J. and Kilau, K. and Richter, M. and Kleint, M. and Ridder, D.A. and Hübner, N. and Schmidt-Supprian, M. and Wenzel, J. and Schwaninger, M.
Abstract:Cerebral small-vessel diseases (SVDs) often follow a progressive course. Little is known about the function of angiogenesis, which potentially induces regression of SVDs. Here, we investigated angiogenesis in a mouse model of incontinentia pigmenti (IP), a genetic disease comprising features of SVD. IP is caused by inactivating mutations of Nemo, the essential component of NF-κB signaling. When deleting Nemo in the majority of brain endothelial cells (Nemo(beKO) mice), the transcriptional profile of vessels indicated cell proliferation. Brain endothelial cells expressed Ki67 and showed signs of DNA synthesis. In addition to cell proliferation, we observed sprouting and intussusceptive angiogenesis in Nemo(beKO) mice. Angiogenesis occurred in all segments of the vasculature and in proximity to vessel rarefaction and tissue hypoxia. Apparently, NEMO was required for productive angiogenesis because endothelial cells that had escaped Nemo inactivation showed a higher proliferation rate than Nemo-deficient cells. Therefore, newborn endothelial cells were particularly vulnerable to ongoing recombination. When we interfered with productive angiogenesis by inducing ongoing ablation of Nemo, mice did not recover from IP manifestations but rather showed severe functional deficits. In summary, the data demonstrate that angiogenesis is present in this model of SVD and suggest that it may counterbalance the loss of vessels.
Keywords:Angiogenesis, Incontinentia Pigmenti, Small Vessel Disease, NF-κB, Endothelial Cell, Angiogenesis Inducing Agents, Brain Ischemia, Animal Disease Models, Endothelial Cells, Intracellular Signaling Peptides and Proteins, Knockout Mice, NF-kappa B, Physiologic Neovascularization, Animals, Mice
Source:Journal of Cerebral Blood Flow and Metabolism
Publisher:Sage Publications
Page Range:219-235
Date:1 February 2021
Additional Information:Copyright © The Author(s) 2020
Official Publication:https://doi.org/10.1177/0271678X20910522
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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