Vascular Functions in Metabolic and CNS Diseases – Ulf Eriksson group

Our research explores the roles of vascular growth factors in regulating vascular integrity, lipid homeostasis and organ function. We investigate how these factors contribute to conditions such as ischemic stroke, diabetic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to translate our research findings into innovative therapeutic strategies for vascular-related disorders across multiple organ systems.

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Department of Medical Biochemistry and Biophysics

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Brain infarction in the vascular territory supplied by the left middle cerebral artery (MCA) after experimental MCA occlusion. Increased vascular leakage (extravasation of a circulating dye, red; vessel marker, white) and lipid accumulation (lipid droplet marker, green) are hallmarks of the acute ischemic cascade (3 hours post ischemia).

We are further exploring this novel activity of tPA in adipose tissue and the influence of elevated circulating fatty acids on cerebrovascular integrity and intracerebral hemorrhage risk. Anti-vascular endothelial growth factor-B (anti-VEGF-B) therapy successfully mitigates intracerebral hemorrhage risk and improves the efficacy of tPA treatment by reducing lipid-induced vascular stress and enhancing endothelial resilience during reperfusion. These findings highlight anti-VEGF-B therapy as a promising co-treatment together with thrombolysis that could significantly influence clinical practices.

The role of PDGF-CC/PDGFRα signaling in modulating blood-brain barrier integrity and fibrotic scar formation after ischemic stroke

Team leader/contact: Linda Fredriksson, PhD (linda.fredriksson@ki.se)

Our research focuses on the role of PDGFRα in ischemic stroke, particularly its impact on blood-brain barrier (BBB) integrity and fibrosis. BBB breakdown is a hallmark of ischemic stroke and is linked to poor clinical prognosis. We have shown that activation of PDGF-CC, the ligand of PDGFRα, by tissue plasminogen activator (tPA) disrupts BBB integrity during ischemic stroke, suggesting that PDGFRα signaling modulation could be a promising therapeutic strategy (Su et al. 2008, Nature Medicine). Based on these findings, a phase II clinical trial evaluated the safety and efficacy of imatinib, an inhibitor of PDGFRα and other receptor tyrosine kinases, in acute ischemic stroke patients treated with intravenous thrombolysis (IVT). The trial demonstrated promising results (Wahlgren et al. 2017, Journal of Internal Medicine) and will be followed by a phase III clinical trial. Furthermore, we recently demonstrated that inhibiting PDGFRα reduces myofibroblast expansion in the fibrotic scar during the chronic phase of ischemic stroke, significantly improving recovery—even when inhibition was initiated 24 hours post-occlusion (Protzmann et al. 2025, Journal of Clinical Investigations). These findings suggest that targeting PDGFRα could serve as a viable post-acute treatment strategy for stroke recovery, addressing a critical gap where current interventions are limited to rehabilitation therapy. Current projects in the lab investigate the use of a monoclonal anti-PDGF-CC antibody (Li et al. 2018, PLoS One; Zeitelhofer et al. 2018, PLoS One) as a targeted approach to block PDGFRα signaling in ischemic stroke, as well as potential progenitors of PDGFRα⁺ myofibroblasts contributing to fibrotic scar formation.

(A) The myofibroblast scar (PDGFRα, green) is located at the rim of the fibrotic core adjacent to the astroglia scar (GFAP, red). (B-D) Myofibroblasts (PDGFRα, green) are characterized by co-expression of α-smooth muscle actin (ASMA, red (B)), PDGFRβ (magenta (C)) and deposition of the extracellular matrix protein fibronectin (FN, red (D)). The size of the PDGFRα+ myofibroblast scar is significantly reduced after imatinib or anti-PDGF-CC antibody treatment (outlined with dashed line in A and D), while the size of the PDGFRβ+ scar remains unaffected (outlined with dashed line in C).

Intravital imaging of the cerebrovasculature in ischemic stroke

Team leader/contact: Linda Fredriksson, PhD (linda.fredriksson@ki.se)

In our lab, we have set up advanced two-photon imaging of photothrombotic ischemic stroke through a chronic cranial window to track BBB integrity, hemodynamic changes and cellular responses of cells in the neurovascular unit (NVU) in real time (Protzmann et al. 2024, Fluids and Barriers of the CNS). We employ a variety of reporter mouse lines (labeling endothelial cells in the vessel wall or other cells of the NVU) and intravenously (i.v.) administered fluorescent dyes in combination with genetic and pharmacologic inhibition of PDGF-CC/PDGFRα signaling to shed light on the blood-brain barrier after ischemic stroke. This technology allows us to longitudinally elucidate and correlate key mechanisms of vascular dysfunction from the early critical hours to the days/weeks after the infarct. A current project in the lab focuses on in-depth studies of intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (tPA) under different conditions by visualizing it in real time at an unprecedented resolution.

Video: Real-time two-photon imaging of IVT with tPA in an endothelial reporter mouse (Claudin5-GFP) that was subjected to experimental ischemic stroke. Blood flow was visualized with the fluorescent tracer TRITC70 (red). The occluded middle cerebral artery (MCA) can be seen in the center of the video. tPA was administered i.v. 35 min after vessel occlusion. Blood clot lysis and re-establishment of blood flow can be seen 145 min post ischemia.

Mechanisms of endothelial nutrient transport

Team leader/contact: Ingrid Nilsson, PhD (ingrid.nilsson@ki.se)

Endothelial cells line the inner wall of all blood vessels and take an active part in the delivery of nutrients, primarily fatty acids and glucose, to the underlying tissues.

Intravital two-photon imaging through a cranial window. Differential dynamics of fatty acid uptake (fatty acid tracer, white) in brain cortex of an individual mouse after eating (upper panels), compared to after overnight fasting (lower panels).

This is a highly regulated process, and we have previously shown that tissues can instruct the local vascular bed to upregulate endothelial fatty acid uptake from blood by increasing the expression of vascular endothelial growth factor-B (VEGF-B) that acts via its receptors, VEGFR1 and neuropilin-1, on endothelial cells. By combining biochemistry and molecular biology techniques, our current research aims to discover novel mechanisms that link trans-endothelial fatty acid transport to intra-endothelial lipid droplet metabolism and cellular bioenergetics. We are especially interested in studying the process of cerebrovascular fatty acid uptake and its consequences for brain health.