Challenge Workshop
June 28-July 2, 2026
Director: Martin Dichgans
LMU Klinikum, Munich, Germany
Faculty:
Richard Daneman, University of California, San Diego, USA
Susanne van Veluw, University of Edinburgh, UK
Andy Shih, Seattle Children’s Hospital, Seattle, USA
Anne Joutel, Institute of Psychiatry and Neurosciences of Paris, France
Fabrice Dabertrand, University of Colorado, Anschutz, USA
David Attwell, University College London, UK
Cerebral small vessel disease (SVD) accounts for a quarter of ischemic strokes, most hemorrhagic strokes, and contributes to at least 40% of dementias. Recent genetic and multi-omic discoveries along with experimental breakthroughs have refined our understanding of the molecular, cellular, and physiological underpinnings of SVD. Endothelial dysfunction has emerged as a major hallmark, with altered ion channel signaling, impaired metabolic coupling, and disrupted communication between brain endothelial cells (BECs), mural cells, astrocytes, and immune cells. High-resolution imaging and single-cell transcriptomic studies have revealed zonated endothelial and mural cell phenotypes along the arteriole-capillary-venous axis—including hotspots for barrier failure, hemodynamic regulation, and disease initiation. Parallel advances have implicated extracellular matrix remodeling, proteostatic stress, and neuroimmune activation as amplifiers of microvascular injury. Integration of these pathways with recent insights into compartmentalized cellular networks now offers unprecedented opportunities to delineate causal mechanisms and therapeutic entry points. This Challenge Workshop will bring together leading experts across vascular biology, genetics, physiology, and pharmacology to synthesize current concepts, identify shared mechanisms across forms of SVD, and chart a path toward rational therapeutic testing.
David Attwell
Small vessel disease: cerebral blood flow, toxic protein removal and myelinated axon damage
Small vessel disease may involve decreased cerebral blood flow (CBF), slowed clearance of toxic proteins such as amyloid beta from the brain, and damage to myelinated axons. During this session, studies examining each of these aspects will be described.
In humans and APPNL-G-F mice, Alzheimer’s disease causes a reduction in cerebral blood flow (CBF) due to amyloid beta triggering pericyte-mediated capillary constriction. This results in tissue hypoxia, which can be reversed by administering the L-type voltage-gated calcium channel blocker nimodipine to enhance blood flow. In human small vessel disease, the use of repurposed drugs cilostazol and isosorbide mononitrate—both expected to relax blood vessels—leads to improved cognitive function. Maintaining brain energy supply is, therefore, likely a crucial factor in preventing cognitive decline.
In recent years, there has been immense controversy over whether toxic amyloid beta and tau proteins, in addition to leaving the brain across endothelial cells, can exit via lymph vessels or via a so-called glymphatic system, facilitated by a water flux through astrocyte endfeet. I will present data in favour of lymph over glymph and provide some evidence for the pathway involved.
White matter hyperintensities on MRI images correlate with cognitive decline and reduced blood flow in small vessel disease, but their origin remains poorly understood. We find that either ischaemia or amyloid beta causes elongation of the node of Ranvier in myelinated axons, followed by enzyme-induced disruption of the paranodal structure, leading to myelin loss. We are testing whether inhibiting the culprit enzyme can protect the myelin and, consequently, cognition.
Martin Dichgans
SVD: from genomic discoveries to biology and targeted interventions
SVD arises from convergent insults to the neurovascular unit, yet the mechanistic links between genetic risk factors and microvascular injury remain incompletely defined. We recently showed that FOXF2 a major risk gene for SVD and stroke functions as a transcriptional activator of endothelial Tie2 signaling. Using endothelial-specific Foxf2 deletion in adult mice, combined with RNA-seq, ChIP-seq, and proteomics, we identified a role for FOXF2 in maintaining BBB integrity, endothelial nitric oxide production, and functional hyperemia. Loss of FOXF2 compromises barrier stability, sensitizes the vasculature to ischemic injury, and enlarges infarct size after experimental stroke. These in vivo phenotypes are recapitulated in a fully human iPSC-derived, perfusable 3D BBB-on-chip model that allows direct comparison of FOXF2-deficient and rescued endothelial states.
Tie2 activation with the small-molecule agonist AKB-9778 reverses the adverse effects of Foxf2 deficiency on BBB leakage, neurovascular coupling, and stroke outcome—even when initiated after stroke onset—underscoring the tractability of Tie2 as a therapeutic target in SVD. Complementing these insights, large-scale human genetic analyses expand our understanding of HTRA1 biology. Rare loss-of-function HTRA1 variants elevate the risk of ischemic stroke, SVD, and large artery disease, while a common regulatory variant affecting circulating HTRA1 levels exerts pleiotropic effects across vascular, neurological, and ocular phenotypes. Biochemical studies demonstrate that impaired protease function underlies many of these associations, highlighting two distinct pathogenic mechanisms: reduced enzymatic activity and altered expression dynamics. Together, these findings support an integrated model in which endothelial dysfunction, extracellular matrix dysregulation, and proteostatic stress act as interconnected drivers of SVD pathogenesis.
Richard Daneman
Blood-brain barrier regulation of brain function and behavior
The properties of the blood-brain barrier (BBB) are manifested in vascular endothelial cells. However, transplantation studies have shown that the BBB is not intrinsic to the endothelial cells themselves but is induced by interactions with neural cells. How does the BBB form during development? How does the BBB regulate brain function and behaviour? How does BBB dysfunction contribute to neurological and neurodegenerative diseases?
To address these issues, we utilise a genomic, genetic, and molecular approach. We have identified key cellular and molecular mechanisms that drive BBB formation, including a critical role for CNS pericytes in modulating BBB function. Furthermore, we have discovered that the BBB is not a static structure but a dynamic component of neural circuitry that responds to changes in neural activity, diet, and exercise. This evidence indicates that the BBB is a critical modulator of neurotransmitter levels in the brain, including glutamate and dopamine, and that this regulation is vital for proper brain function and behaviour. Finally, we have shown that BBB dysfunction leads to a loss of neurovascular fatty acid metabolism, an important factor in modulating the brain’s neuroinflammatory environment. Collectively, these findings underscore the immense importance of the BBB in shaping the brain’s environment during development, health, and disease.
Fabrice Dabertrand
Cortical blood flow redistribution in small vessel disease
Cerebral hemodynamic dysfunction is a key driver of unhealthy brain aging. Impaired microcirculatory reactivity leads to uneven perfusion, making deeper brain regions more vulnerable and ultimately leading to cognitive decline. However, the precise mechanisms by which capillaries and their associated cells, known as pericytes, contribute to these deficits are not well understood. We combined spatial transcriptomics with in vivo two- and three-photon imaging to quantify layer-specific cerebral blood flow in transgenic control and small vessel disease (SVD) model mice. We identified a selective reduction in ATP-synthesising gene expression within the SVD microvasculature, indicating compromised vascular metabolic capacity. This energy deficit was linked to decreased pressure-dependent contractility in the arteriole-to-capillary transition (ACT) zone, a key area where pericytes regulate flow distribution. Complementary ex vivo myography, pericyte electrophysiology, and computational modelling revealed that hyperactive ATP-sensitive potassium (KATP) channels in ACT pericytes redirected blood flow towards superficial layers, producing deep-layer hypoperfusion despite preserved global cerebral blood flow. This redistribution disrupted uniform perfusion across cortical layers, a pattern consistent with the regional vulnerability observed in SVD and mixed dementia. Overall, these findings identify spatial perfusion equalization as a critical yet underrecognized vascular function and establish ACT pericytes as key modulators of layer-specific flow distribution, supporting a model in which metabolic deficits and pericyte dysfunction converge to compromise microvascular resilience and selectively increase vulnerability of deep cortical regions, linking microvascular dysfunction to cognitive impairment.
Anne Joutel
Mural cells: from diversity in the healthy brain to degeneration in cerebral small vessel disease
Mural cells, including smooth muscle cells (SMCs) and pericytes, are vital structural and functional components of brain vessels. Early single-cell transcriptomic studies classified mural cells into two broad classes, yet recent histological and functional studies indicate much greater diversity. Notably, degeneration and loss of arterial SMCs is a consistent feature of both genetic and sporadic forms of cerebral SVD, highlighting a critical, yet understudied aspect of disease pathophysiology.
We have developed novel approaches to comprehensively profile brain mural cells in mice, combining single-cell analyses with precise three-dimensional spatial mapping along the arteriovenous axis and across brain regions. Using this approach, we identified seven transcriptionally distinct mural cell types that align with the arteriovenous continuum from large pial arteries to major veins. SMCs segregate into five separate subtypes, each occupying defined anatomical domains. Notably, we provide the first molecular, cellular, and anatomical characterisation of mural cells at the arteriole–capillary transition zone, revealing a distinct population whose transcriptional pathway links arterial SMCs and pericytes.
By combining proteomic profiling of brain arteries with publicly available datasets, we identified a novel secreted protease as the most consistently upregulated matrisome protein in several cSVD mouse models. Single-cell RNA sequencing revealed that this protease is predominantly expressed by arterial SMCs and endothelial cells. Crucially, genetic suppression of this protease prevents arterial SMC degeneration in cSVD models. Ongoing studies are investigating the mechanistic link between its overexpression and arterial SMC loss.
Susanne van Veluw
Unravelling the mechanisms of amyloid-beta deposition and vascular remodelling in cerebral amyloid angiopathy
Cerebral amyloid angiopathy (CAA) – characterized by the deposition of amyloid-beta in the walls of leptomeningeal arteries, cortical arterioles, and capillaries – is one of the most common forms of cerebral small vessel disease and the leading cause of haemorrhagic stroke in older individuals. Ongoing studies in the lab focus on understanding the mechanisms by which amyloid-beta accumulates in the vessel wall during early stages of disease progression. Specifically, we are zooming in on the role of low-frequency vasomotion in perivascular amyloid-beta clearance and the effects of enhancing vasomotion to improve clearance and preserve vascular health. In parallel, we are investigating the mechanisms underlying vascular remodelling, vessel wall breakdown, and haemorrhage during the later stages of disease progression. A recent digital spatial proteomics study in post-mortem human brain tissue from patients with CAA identified a role for complement activation in disease progression and vascular remodelling, offering a potential target for future intervention strategies.
Andy Shih
Capillary-venous contributions to white matter hypoperfusion during aging and cerebral small vessel disease
Beyond the arterioles that supply blood, extensive networks of capillaries and venules play crucial roles in blood distribution and drainage in the brain. However, there remains limited information on how these vessel types change with aging and across cerebral small vessel diseases (SVD), and whether these changes contribute to damage in vulnerable cerebral white matter. To address these questions, we used deep multiphoton imaging in mouse models to examine microvascular structure and perfusion within callosal white matter. With normal aging, we identified selective vasoconstriction and regression of capillary networks feeding large draining venules in the corpus callosum, leading to mild chronic hypoperfusion. Mimicking this degree of hypoperfusion across a brain hemisphere using carotid artery stenosis is sufficient to induce microgliosis, astrogliosis, and demyelination specifically within white matter. In a mouse model of Type 1 cerebral amyloid angiopathy, similar microvascular changes and hypoperfusion are observed much earlier in the lifespan.
Furthermore, pericyte loss is observed preferentially along peri-venous capillaries and is associated with reduced capillary density and increased resistance to blood flow drainage into venules. To begin identifying causal factors underlying white matter hypoperfusion, we are conducting cellular-resolution spatial transcriptomic analyses of pericytes and endothelial cells across adulthood, midlife, and aging. In parallel, we are developing in vivo approaches to manipulate pericytes to better understand the effects of their pathology. This includes optical cell ablation to model pericyte loss and chemogenetic approaches to chronically engage capillary pericyte contraction and capillary constriction. Together, this work provides converging evidence that impaired perfusion of capillary-venous networks contributes to age- and SVD-related hypoperfusion in mouse white matter and informs future mechanistic studies.