Tissue perfusion and microcirculation

Welcome to our research group dedicated to the fascinating realm of tissue perfusion and microcirculation. At the heart of our work lies the exploration of fundamental mechanisms governing blood flow within the intricate network of tiny blood vessels known as the microcirculation. We delve into the mysteries of perfusion, unraveling the intricate dance between blood, tissues, and the vasculature.

Our mission goes beyond mere understanding; we strive to make a tangible impact on human health. We are deeply committed to addressing pathologies that disrupt the delicate balance of microcirculatory function. One of our primary areas of focus is the cerebral circulation, where we aim to unlock the secrets of blood flow regulation, particularly in the context of stroke, a debilitating and often life-altering condition.

With cutting-edge research and a passionate team, we aim to contribute to the development of innovative therapies and treatments that can improve the lives of individuals affected by ischemic stroke and cerebral microcirculation-related disorders.

Focus

Acute Ischemic stroke

Acute ischemic stroke, often caused by a sudden blockage in a large vessel like the middle cerebral artery, deprives a part of the brain of oxygen and nutrients. Quick intervention is crucial to reduce damage. Mechanical thrombectomy has revolutionized treatment, but still only one out of three patients recovers to independency after successful removal of the thrombus.

Continuing tissue damage and infarct growth in the days after apparently complete clot removal is a major concern. The mechanisms are not fully understood but seem to involve the microcirculation. Processes like arteriolar and capillary spasm, brain edema, microcirculation obstruction, and vascular paralysis may contribute here. Attempts to tackle these processes or protect the brain tissue against ongoing damage have all failed, and a better understanding of these microvascular processes is needed.

We study the microcirculation in mouse models of acute ischemic stroke. We use various models of stroke induction, in particular the transient Middle Cerebral Artery Occlusion model (MCAO). The infarct core and surrounding tissue (penumbra) are imaged by in vivo two-photon microscopy, Laser Speckle Contrast Imaging and MRI, allowing a direct correlation of local vascular events such as spasm and capillary stalling to progression of damage. Our current focus here is on pericyte contraction and capillary stalling.

With this work we participate in the Contrast consortium and Netherlands Experimental Stroke Alliance NESA, supported by the Netherlands Heart Foundation and Dutch Brain Foundation.

In vivo two-photon microscopy

Laser Speckle Contrast Imaging

MRI

Microvascular embolism

Microvascular embolism, caused by small vessel occlusions, may occur as a result of thrombus fragmentation during large vessel occlusion or removal of the clot by thrombectomy. Also in less acute settings, microvascular embolism by micro-thrombi or other particles may occur. We hypothesize that a misbalance between the rates of embolization and embolus clearance leads to chronic loss of microvascular capacity, contributing to cognitive decline. We study the effect of these small emboli on tissue damage and the mechanisms that resolve micro-embolization. We address this in a variety of in vitro systems as well as in vivo in the mouse brain, using two-photon imaging through a cranial window and injection of emboli in the carotid artery. We currently are particularly interested in so-called angiophagy, where emboli transmigrate in the course of days from the vessel lumen to the brain parenchyma, leading to recovery of flow.

This intriguing process of embolus extravasation may have therapeutic potential: in a proof of concept study we demonstrated the extravasation of biodegradable microspheres that have drug-carrying capacity. Transmigration of such microspheres followed by controlled drug release in the brain parenchyma could be a way of passing the blood-brain barrier in severe brain diseases such as glioblastoma.

Arterial network regulation

Arteries in our body that carry much flow have a large diameter. Apparently, vessels are able to sense the flow and adapt their diameter through growth and structural remodeling, leading to an astonishing more than 1000-fold range of diameters, from the aorta to the precapillary arterioles. On top of this, all of these vessel continuously fine-tune their diameter by vasoconstriction or dilation within seconds in order to match blood flow to the oxygen demand. What are the mechanisms of this remarkable capability for diameter adaptation? And why care?

We study arterial network design and adaptation using a variety of approaches:

  • We perform in vitro and in vivo experimental studies on mechanisms of vaso-activity as well as remodeling. Notably, we use isolated, pressurized blood vessels in acute settings to study vaso-activity, and also keep such pressurized vessels in organoid culture to study remodeling.
  • In silico (modeling and simulation) approaches of arterial network adaptation, focusing on the integrative aspect: the arterial segments within a network communicate to perform their task of diameter and flow adaptation. This communication is based on hemodynamic interaction as well as direct electrical communication. Building models of this helps us to better understand network behavior and identify critical processes that then can lead to new experimental designs.

We perform this work for several reasons

  • Dysregulation is a hallmark of many pathologies: hypertension, microvascular maladaptation in ischemic heart diseases and following stroke, shock, renal failure, and many more. Understanding arterial diameter regulation is crucial for better insight into the pathogenesis of these diseases and for development of new treatment options.
  • Artificial organs based on tissue engineering require a functional vascular network once their size exceeds a millimeter. Knowledge on arterial network adaptation may help developing techniques for vascularized artificial organs.
  • There is a surge in digital twin developments. Realistic simulation models of patients are increasingly used for drug and device development and optimization of new RCT. Realistic vascular networks need to be generated here, typically based on combinations of actual data and rule-based network generation.
Output

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