"Neurovascular regulation of transport at the blood-brain barrier"

Abstract:

The need for new treatments of brain diseases is growing with the increasing lifespan of western populations. However, drug transport across the blood-brain barrier (BBB) is a great challenge because of the low permeability of the barrier. This presentation will outline key mechanisms for transporting cargo across the BBB in vivo as applied to normal brains, brains with low levels of activity at the sphingosine-1-receptor and in the 5XFAD model of Alzheimer’s disease. Our recent work has outlined new methodologies to quantify paracellular transport in brain arterioles and capillaries, adsorption mediated transcytosis (AMT), receptor mediated transcytosis (RMT) and the density of glycocalyx in cortical microvessels in vivo. This enables us to provide a detailed analysis of mechanisms and pharmacokinetics of drugs and drug vehicles in health and disease. Our work has revealed a segregation of transport functions along the microcirculation from the arteriolar to the venous end of the vascular tree. Furthermore, we have developed new tools to examine trafficking of large molecules and drug carriers in brain extracellular space, which enables us to assess drug bioavailability in brain tissue and important aspects of pharmacodynamics. Our projects combine research on drug transport systems with research on BBB and the neurovascular unit. The prospect of this work is to make a breakthrough in mechanistic insight to the functional organization of the BBB, and to push boundaries in the universal efforts to influence drug delivery across the BBB for the benefit of patients.

Biography:

Professor Martin Lauritzen has been a pioneering clinician-scientist in the field of cerebrovascular biology for over four decades. He has worked on our understanding of neurovascular functions, including the blood-brain barrier (BBB) and the role of cortical spreading depolarization/depression (CSD) in migraine and acute brain injury. His first major contribution was his early work on migraine, and CSD as the mechanism of this neurological disorder, and later he focused on the role of CSDs in acute neurologic injury. A second major focus of Martin’s research program has been the mechanistic understanding of neurovascular coupling, i.e. the regulation of cerebral blood flow (CBF) by neural activity and the generation of functional Magnetic Resonance Imaging (fMRI) signals in health, aging and disease. Martin has development of advanced new imaging and image analysis tools for multimodal measurements of brain activity that underlie the cellular and molecular origin of neurovascular coupling. A third and recent focus is the exploration of the BBB by multiphoton microscopy and the quantification of permeability characteristics along para- and transcellular pathways. Martin’s lab operates at the interface between neuroscience and clinical neurology, bridging the worlds of biology and technology, advancing measurement methods, and applying novel methods for addressing central neuroscience questions relevant for neurovascular physiology, regulation of CBF and metabolism, and the interpretation of findings in brain aging and disease states.

Top 6 publications from 2018-2023:

• Cai C et al. . Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain. Nature Aging 2023, DOI 1038/s43587-022-00354-1
• Kucharz K et al. Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic Nat Comm 2021 Jul 5; 12(1):4121. doi: 10.1038/s41467-021-24323-1.
• Zambach SA et al. Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion. Proc Natl Acad Sci U S A 2021, DOI number 10.1073/pnas.2023749118.
• Grubb S et al.. Precapillary sphincters maintain perfusion in the cerebral cortex. Nat Commun. 2020 Jan 20; 11(1):395. doi: 10.1038/s41467-020-14330-z. PMID: 31959752.
• Cai C et al. Conducted vascular responses in brain capillaries by synaptic activity and ATP in mouse cerebral cortex. Proc Natl Acad Sci U S A. 2018 Jun 19; 115(25):E5796-E5804. oi:.1073/pnas.1707702115. PMID: 29866853. 
• Kutuzov N et al.. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood-brain barrier. Proc Natl Acad Sci U S A. 2018 Oct 2; 115(40):E9429-E9438. doi: 10.1073/pnas.1802155115.