International Network of Excellence on Brain Endothelium
A Nexus for Cerebral Small Vessel Disease
Background
Cerebral small vessel disease (SVD) is a very common progressive vascular disease that covers various pathologies all related to the small vessels in the brain. Due to damage or malfunction of these tiny vessels, the cerebral blood-low is reduced leading to chronic damage of tissue over the years.
SVD is a major cause of microinfarcts and microbleeds-types of stroke that often go undetected, but are major contributors to disability and dementia. Despite such a profound impact on brain health, there are no proven treatments for SVD that can prevent, or slow down the progression of this disease. Treatment is currently limited to reducing common vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking. Additional main risk factors are advanced age and genetic factors.
The underlying pathomechanisms of this disease are still not understood. However, hypertension as the leading risk factor and vascular endothelial dysfunction are clearly associated with cSVD. Brain endothelial cells (BECs) have unique roles at the blood-brain barrier (BBB) and in controlling cerebral blood flow (CBF), including sensing moment-to-moment changes in neural activity. We propose this essential integrator function is progressively degraded in SVD and that microvascular BEC dysfunction serves as a nexus for the loss of brain health.
Yet, we have only scratched the surface in understanding the contribution of BECs to vascular control and brain health. Investigators of this network have identified genetic variants in humans that increase the risk for SVD and stroke. In addition, they have developed mice that express such variants in BECs and have shown that they exhibit SVD and brain injury that mimic those in humans. Our preliminary results suggest that, when combined with genetic variants in BECs, hypertension increases SVD and brain injury to a greater extent than either pathology alone.
Objectives
The BRENDA network aims to investigate the BEC-specific mechanisms underlying SVD, ischemic stroke, and intracerebral hemorrhage. Our overarching hypothesis is that BECs have an initiating role in SVD and that genetic predisposition combined with hypertension synergistically drive SVD (two-hit model).
Our overall objective is to identify novel pathways and targets for treatment, with the goal of preventing the decline in brain health.
We will combine unique complementary expertise to pursue three highly integrated aims:
Aim 1: Define the mechanisms linking risk genes for SVD & stroke to BEC dysfunction and brain injury.
Aim 2: Test the hypothesis that hypertension synergizes with stroke-risk genes to augment BEC dysfunction and brain injury (“two-hit” model).
Aim 3: Unveil the contribution of BEC heterogeneity to vascular function and brain health.
The Network
The interdisciplinary network brings together seven basic researchers and clinician scientists with expertise in genetics, cell biology, electrophysiology, RNA seq, optical imaging and stem cell biology. The team is complemented by postdoctoral fellows and graduate students in each lab.
Coordinators
Principal Investigators
News
Network News, Events & Open Positions
Sep 30-Oct 2, 2024: 4th Project Meeting, Burlington, USA
The meeting was hosted by Mark Nelson’s group in Vermont. Again it was a complete success, featuring great presentations, a workshop on 4D image analysis and collaborative brainstorming mainly led by the early career investigators. In the meantime the BRENDA network have truly grown into a cohesive team
Virtual Seminar Series
October 7, 2024
Dritan Agalliu is interested in the cellular and molecular mechanisms that regulate the formation of the blood-brain barrier in the central nervous system and the mechanisms of barrier breakdown in a variety of CNS diseases. His group has developed novel mouse strains that allows to visualize changes in structural components of the blood-brain barrier, namely tight junctions and caveolae, in living animals for several CNS diseases (e.g. stroke and multiple sclerosis).
Guest speaker:
Dritan Agalliu
Associated Professor, Columbia University, New York
“Mechanisms of Angiogenesis and Neurovascular Barrier Development, Breakdown and Repair in the Central Nervous System”
Virtual Seminar Series
August 6, 2024
Michael Potente and his team focus on the human vasculature network, how it develops and remodels and how its function is disrupted in diseases. They uncovered essential metabolic pathways limiting blood vessel expansion and described the forkhead transcription factor FOXO1 as a central coordinator of these programs.
Guest speaker:
Michael Potente
Professor, Max Delbrück Center, Charité Berlin
“Development under metabolic stress: How endothelial cells form and function in challenging tissue environments”
Virtual Seminar Series
July 2, 2024
Jason Berwick’s group uses multimodal neuroimaging and electrophysiological techniques to measure and understand neurovascular coupling in health and disease with a focus on mouse models of Alzheimer’s disease.
Guest speaker:
Jason Berwick
University of Sheffield
“Neurovascular coupling breakdown in neurodegenerative disease”
Virtual Seminar Series
June 4, 2024
Catherine Hall is interested in how the brain balances energy supply and demand. Small decreases in brain blood flow happen in several diseases and are likely to be important drivers of pathology – for example, in Alzheimer’s disease. They image blood vessels in brain slices and in vivo, in behaving mice, while manipulating neuronal activity. Together these measurements provide a rich understanding of how the brain changes at the onset of disease or when oxygen supply is reduced.
Guest speaker:
Catherine Hall
Professor, Brain Energy Lab, University of Sussex in Brighton
“How does the brain regulate its energy supply? Neurovascular coupling and the impact of a failure to match energy supply and demand”
May 13-15, 2024: 3rd Project Meeting, Rånäs Slott, Sweden
The meeting took place in the lovely castle Rånäs Slott close to Stockholm. Beside talks of the different groups we had a very interesting workshop on transcriptomics and further stimulating discussions.
Virtual Seminar Series
May 7, 2024
Cerebral Cavernous Malformation (CCM) is a disease in which abnormally dilated and tortuous blood vessels form vascular malformations predominantly in the brain. About 9% of patients also suffer from vascular malformations in the skin. Konstantin and his team developed for the first time a mouse model of CCM skin lesions that allows to study disease mechanisms at single cell resolution in living animals in real time. It also opens exciting possibilities as it, for example, permits, to investigate the effects of potential drugs on lesion growth or lesion regression.
Guest speaker:
Konstantin Gängel
Assistant Professor, University of Uppsala
"A mouse model of Cerebral Cavernous Malformation that recapitulates human vascular skin lesions and allows intravital imaging of disease mechanisms"
Virtual Seminar Series
April 2, 2024
Kari Alitalo is working on vascular endothelial growth factors and receptors that he has discovered. He and his group focus on their preclinical and translational use in studies to restore homeostasis and to improve tissue functions in cardiovascular disease and several other human diseases. In his recent work he explored the atheroprotective role of Tie2 in arterial endothelium.
Guest speaker:
Kari Alitalo
Professor, University of Helsinki, Finnland
"Translational insights into vascular growth factors"
Virtual Seminar Series
March 5, 2024
Aernout Luttun is interested in the heterogeneity in the cardiovascular system, and how this is regulated by genetic and environmental factors. He and his group have identified several transcription factors that are highly enriched in endothelial cells of different vascular territories
Guest speaker:
Aernout Luttun
Professor, KU Leuven, Belgium
"Transcriptional regulation of endothelial heterogeneity in health and disease"
Virtual Seminar Series
February 6, 2024
To better understand the relationship between the metabolic need of the different neural cell types and the topology of the adult vascular network, Nicolas Renier and his team built a 3D developmental atlas of the brain vasculature. He will talk about the vascular network, how it can cater differently to the metabolic needs of both the developing and adult brain, and how cerebral networks shape the development and maintenance of the cerebral vasculature.
Guest speaker:
Nicolas Renier
Laboratoire de Plasticité structurale, ICM, Paris
"The developing post-natal cerebral vasculature"
Virtual Seminar Series
January 9, 2024
Serge Charpak and his team aims to develop new imaging tools that allow investigating brain activity at cellular level. In particular he is interested in the modulation of brain network activity between neurons and non-neuronal cells.
Guest speaker:
Serge Charpak
Professor, INSERM, Paris
"Neurovascular coupling and brief CO2 interrogate distinct vascular regulations"
Virtual Seminar Series
December 5, 2023
Edith Hamel is interested in neuronal control of local cerebral blood flow and how this relationship is altered in pathologies like Alzheimer’s disease and vascular cognitive impairment and dementia.
Guest speaker:
Edith Hamel
Professor Emerita, Mc Gill University, Montreal, Canada
“Resting-state functional connectivity and neurovascular coupling in Alzheimer’s disease mice through the disease spectrum: Effects of pharmacotherapy.”
Virtual Seminar Series
November 2, 2023
Andy Shih is an expert in advanced optical imaging to study cerebrovascular disease. He will talk on the regulation of cerebral blood flow through capillaries by pericytes.
Guest speaker:
Andy Shih
Associate Professor at Seattle Children’s Research Institute and the University of Washington
"Pericyte roles in maintenance of brain microcirculation during health, aging and small vessel disease"
October 18-20, 2023: 2nd Project Meeting, Munich, Germany
The meeting started with an opening lecture by Fabrice Dabertrand, University of Colorado: “From impaired cerebral blood flow to cognitive impairment“. Following this, the Early Career investigators went downtown for a Munich Experience event.
The following days were filled with stimulating discussion and new ideas for collaborations. The whole team is exicted about the work ahead.
Virtual Seminar Series
September 5, 2023
Martin Lauritzen from University of Copenhagen will be our first guest speaker.
Martin Lauritzen
Professor
University of Copenhagen
“Brain endothelial cells and the blood-brain barrier”
Virtual Seminar Series
July 11, 2023
Rasna Sabharwal, PhD, Assistant Professor in Frank Faraci’s lab and Amreen Mughal, Research Assistant Professor in Mark Nelson’s group will present their work.
Rasna Sabharwal
PhD
University of Iowa
Title: tbd
Amreen Mughal
PhD
University of Vermiont
"Electro-Calcium Coupling and Alzheimer’s disease"
Virtual Seminar Series
June 7, 2023:
Our new BRENDA Virtual Seminar series that will be held once a month will start in June 2023.The seminars alternate between talks from Early Career Investigators (ECI) and presentations from International Speakers. Louise Schröger, PhD student at Martin Dichgans`s lab is the first ECI who will talk about her ongoing work.
Luise Schröger
PhD student
LMU Hospital Munich, Institute for Stroke and Dementia Research
“Neuronal injury in Foxf2-deficient mice associates with iron overload”
March 26-28, 2023: 1st Project Meeting, New York City, USA
The first in-person meeting was hosted in New York. This was for the first time that senior and junior scientists working in BRENDA came together to getting to know each other and to established new collaborations.
Publications
latest publications of the BRENDA Network
Todorov-Völgyi K, González-Gallego J, Müller SA, Beaufort N, Malik R, Schifferer M, Todorov MI, Crusius D, Robinson S, Schmidt A, Körbelin J, Bareyre F, Ertürk A, Haass C, Simons M, Paquet D, Lichtenthaler SF, Dichgans M. Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging. Nat Aging. 2024 Mar 22. doi: 10.1038/s43587-024-00598-z. Epub ahead of print.
Faraci FM, Scheer FAJL. Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure. Circ Res. 2024 Mar 15;134(6):810-832. doi: 10.1161/CIRCRESAHA.124.323515. Epub 2024 Mar 14.
Lo EH, Faraci FM. Circadian Mechanisms in Cardiovascular and Cerebrovascular Disease. Circ Res. 2024 Mar 15;134(6):615-617. doi: 10.1161/CIRCRESAHA.124.324462. Epub 2024 Mar 14.
Vázquez-Liébanas E, Mocci G, Li W, Laviña B, Reddy A, O'Connor C, Hudson N, Elbeck Z, Nikoloudis I, Gaengel K, Vanlandewijck M, Campbell M, Betsholtz C, Mäe MA. Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage. Cell Rep. 2024 Mar 5;43(3):113911. doi: 10.1016/j.celrep.2024.113911. Epub ahead of print.
Prapiadou S, Živković L, Thorand B, George MJ, van der Laan SW, Malik R, Herder C, Koenig W, Ueland T, Kleveland O, Aukrust P, Gullestad L, Bernhagen J, Pasterkamp G, Peters A, Hingorani AD, Rosand J, Dichgans M, Anderson CD, Georgakis MK. Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis. Circulation. 2024 Feb 27;149(9):669-683. doi: 10.1161/CIRCULATIONAHA.123.064974. Epub 2023 Dec 28.
Dupré N, Gueniot F, Domenga-Denier V, Dubosclard V, Nilles C, Hill-Eubanks D, Morgenthaler-Roth C, Nelson MT, Keime C, Danglot L, Joutel A. Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL. J Clin Invest. 2024 Feb 22:e175789. doi: 10.1172/JCI175789. Epub ahead of print.
Mughal A, Sackheim AM, Koide M, Bonson G, Ebner G, Hennig G, Lockette W, Nelson MT, Freeman K. Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature. J Cereb Blood Flow Metab. 2024 Feb 29:271678X241235790. doi: 10.1177/0271678X241235790. Epub ahead of print.
Filler J, Georgakis MK, Dichgans M. Risk factors for cognitive impairment and dementia after stroke: a systematic review and meta-analysis. Lancet Healthy Longev. 2024 Jan;5(1):e31-e44. doi: 10.1016/S2666-7568(23)00217-9. Epub 2023 Dec 12.
Dichgans M, Malik R, Beaufort N, Tanaka K, Georgakis M, He Y, Koido M, Terao C, Anderson C, Kamatani Y. Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease. Res Sq [Preprint]. 2023 Nov 7:rs.3.rs-3523612. doi: 10.21203/rs.3.rs-3523612/v1.
Kopczak A, Stringer MS, van den Brink H, Kerkhofs D, Blair GW, van Dinther M, Reyes CA, Garcia DJ, Onkenhout L, Wartolowska KA, Thrippleton MJ, Kampaite A, Duering M, Staals J, Lesnik-Oberstein S, Muir KW, Middeke M, Norrving B, Bousser MG, Mansmann U, Rothwell PM, Doubal FN, van Oostenbrugge R, Biessels GJ, Webb AJS, Wardlaw JM, Dichgans M; TREAT-SVDs collaborators. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. Lancet Neurol. 2023 Nov;22(11):991-1004. doi: 10.1016/S1474-4422(23)00293-4.
Dichgans M, Faraci FM; BRENDA Network. Brain endothelium: a nexus for cerebral small vessel disease. Eur Heart J. 2023 Oct 21;44(40):4211-4213. doi: 10.1093/eurheartj/ehad526.
Taylor JL, Walsh KR, Mosneag IE, Danby TGE, Luka N, Chanda B, Schiessl I, Dunne RA, Hill-Eubanks D, Hennig GW, Allan SM, Nelson MT*, Greenstein AS, Pritchard HAT. Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia. Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2307513120. doi: 10.1073/pnas.2307513120. Epub 2023 Aug 7. *Corresponding author
Shahsavarani S, Thibodeaux DN, Xu W, Kim SH, Lodgher F, Nwokeabia C, Cambareri M, Yagielski AJ, Zhao HT, Handwerker DA, Gonzalez-Castillo J, Bandettini PA, Hillman EMC. Cortex-wide neural dynamics predict behavioral states and provide a neural basis for resting-state dynamic functional connectivity. Cell Rep. 2023 Jun 27;42(6):112527. doi: 10.1016/j.celrep.2023.112527. Epub 2023 May 26.
Faraci FM. Endotheliopathy: Additional Players Slow the Downward Spiral. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):852-854. doi: 10.1161/ATVBAHA.123.319285. Epub 2023 Apr 20.
Klug NR, Sancho M, Gonzales AL, Heppner TJ, O'Brien RIC, Hill-Eubanks D, Nelson MT. Intraluminal pressure elevates intracellular calcium and contracts CNS pericytes: Role of voltage-dependent calcium channels Proc Natl Acad Sci U S A. 2023 Feb 28;120(9):e2216421120. doi: 10.1073/pnas.2216421120. Epub 2023 Feb 21.
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