Bone morphogenetic protein-dependent regulation of the retinal neurovascular unit
Developmental Neurobiology
Final Report Abstract
Brain physiology relies on a functional blood-brain barrier that controls the exchange of molecules between the blood circulation and the surrounding brain tissues. Loss of blood-brain barrier integrity is observed in numerous neurovascular disorders, including stroke and neurodegenerative diseases like Alzheimer’s disease. Thus, understanding how the barrier and its structural component, the neurovascular unit, develop and function is critical to develop effective therapeutic strategies. In this research project, I addressed the role of bone morphogenetic protein (BMP) signaling in development and function of the retinal neurovascular unit. The retinal neurovascular unit is comprised of endothelial cells, astrocytes and retinal ganglion cells and since the retina is a specialized part of the forebrain, it is an excellent model system to study mammalian neurovascular development. Based on our previous study on the role of BMP6 in regulating barrier integrity, I first investigated the expression and function of BMP6 during retinal development. BMP6 was expressed by endothelial and peri-endothelial cells at early stages of development, while it was expressed by retinal ganglion cells at later stages of development. Injection of recombinant BMP6 resulted in increased vascular leakage in the developed retina. These findings are in line with our previous in vitro observations, thereby highlighting BMP6 as a potent permeability-inducing factor in vivo and in vitro. However, light-induced neurovascular coupling in the presence of BMP6 resulted in inconclusive observations, indicating a complex interplay between BMP6 signaling and neurovascular coupling in the developed retina. Using a BMP-SMAD reporter mouse, I identified endothelial cells as the main BMP responsive cell type within the retinal neurovascular unit. Based on these findings, I further investigated the role of BMP- SMAD1/5 signaling in endothelial cells during retinal development using a conditional knockout mouse model. Upon deletion of Smad1/5 in endothelial cells, arteriovenous malformations form at early stages of development. Furthermore, I demonstrated that endothelial SMAD1/5 signaling regulates retinal blood vessel formation and vascular remodelling, thereby largely affecting the endothelial compartment of the developing neurovascular unit. However, endothelial SMAD1/5 had only a minor, if any, function in the developed neurovascular unit as no morphological changes were observed, indicating a developmental stage-dependent role of BMP-SMAD1/5 signaling. Interestingly, we identified endothelial SMAD1/5- dependent signaling as a major regulator of bone marrow vasculature formation during late postnatal development. This project was performed in collaboration with Berlin and Leuven based scientists and will be pursued in the future to address the role of endothelial BMP-SMAD1/5 signaling in bone fracture healing and osteoporosis. The data obtained during my research stay at the KU Leuven clearly demonstrates that BMP6 and SMAD1/5-dependent signaling are required for vascular development and function in the retinal neurovascular unit. Therefore, I accomplished to address the major objectives of this research project during my DFG-funded research period. I unraveled (I) the role of BMP6 during retinal neurovascular development and function; and (II) the function of SMAD1/5 during retinal blood vessel formation and blood-retina barrier integrity. Furthermore, I established numerous methods in the host lab that can be used in future studies by me or my collaboration partners. Our data highlight potential therapeutic targets for blood vessel-associated pathologies, such as hereditary hemorrhagic telangiectasia, as well as neurovascular disorders, including ischemia and Alzheimer’s disease. Further studies are required to address the underlying molecular mechanisms to pave the way for more effective therapeutic strategies.
Publications
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Physiological and pathological consequences of vascular BMP signaling. S. Vukicevic, K. Sampath (eds.), Bone Morphogenetic Proteins: Systems Biology Regulators, Progress in Inflammation Research. Springer (Switzerland). 2017
Benn A, Haupt J, Hildebrandt S, Kaehler C, and Knaus, P
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Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signalling pathways balance stalk vs tip cell competence. FASEB J. 2017; 31(11):4720-4733
Benn A, Hiepen C, Osterland M, Schütte C, Zwijsen A, Knaus P
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Sex-specific metabolic and functional differences in human umbilical cord vein endothelial cells from twin pairs. Atherosclerosis. 2019
Lorenz M, Benn A, Blaschke B, Hammer E, Witt E, Kirwan J, Fritsche-Guenther R, Gloaguen Y, Bartsch C, Vietzke A, Kramer F, Kappert K, Brunner P, Nguyen HG, Dreger H, Stangl K, Knaus P, Stangl V
