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The mammalian brain depends on a well-controlled delivery of nutrients and oxygen in order to function properly. These components reach the brain via the blood circulation through a network of cerebral arteries, arterioles and capillaries. Obstructions of the cerebral vasculature can cause disturbance of homeostasis and lead to severe neurological deficits. In this thesis we evaluated the spatiotemporal effects of multiple occlusions at the arteriole level on brain tissue and investigated intrinsic mechanisms of blood flow restoration and debris clearance. Chapter 1 forms an introduction to the thesis. In chapter 2 the impact of occlusions on brain tissue perfusion and oxygenation is studied by using both in vivo and in silico approaches. In chapter 3 , we studied the spatial relationship between occlusion site and the induced hypoxic or infarcted regions. In chapter 4 we monitored and quantified brain lesions in terms of ischemia, hypoxia and infarction for a period of seven days. Possible recovery mechanisms were investigated in the following chapters. Chapter 5 focuses on the blood brain barrier (BBB) disruption, a severe complication of (micro-) occlusions and on the mechanisms that restore homeostasis. In chapter 6 , we studied angiophagy, the extravasation of microspheres to the brain parenchyma, using both in-vitro and in-vivo experiments. Since microemboli are actively transferred to the brain parenchyma through angiophagy, we investigated in chapter 7 whether this mechanism can be exploited for the transfer of therapeutic compounds through the BBB. Finally, the findings of this thesis, future perspectives and conclusions are presented in chapter 8 .

Remodeling of the vascular wall occurs in several cardiovascular pathologies. A structural change in diameter necessarily involves reorganization in both cellular and extracellular matrix components. The significance of matrix remodeling in vascular pathologies is well appreciated, while plasticity of vascular smooth muscle cells (SMC) received less attention. Such contractile plasticity is defined as a change of the diameter-dependent capacity for active force generation. The aim of this thesis is to investigate how small arteries maintain their stability and functionality, from a biomechanical perspective, during physiological and pathological remodeling. We propose that vascular SMC plasticity is an important process in inward remodeling of small arteries. The most important findings were; the contractile properties of SMCs in resistance vessels are subject to rapid changes. Such contractile plasticity is influenced by externally imposed vasoconstriction and strain. Vasoconstrictors and specifically ET-1 induced inward SMC plasticity in small arteries while chronic strain results a shift of tension generating capacity to larger diameters. This process may maintain optimal matching of SMC and matrix biomechanics during growth and remodeling. The work contributes to a better understanding of vascular wall biomechanics and adaptation, and may lead to new options for diagnosis and treatment of cardiovascular diseases.

Mensen van Afrikaanse afkomst uit gebieden ten zuiden van de Sahara hebben door onbekende oorzaak een verhoogde bloeddruk. Zhila Taherzadeh vond dat de kleine vaten van mensen uit deze groep anders reageren op stimulatie, bijvoorbeeld door het sympathisch zenuwstelsel. Er is sprake van verhoogde samentrekking van de vaten, waarbij het energiegenererende enzym creatinekinase (CK) een belangrijke rol lijkt te spelen. Dit is onderzocht bij zwangere en niet-zwangere vrouwen, en bij muizen. Daarnaast vond Taherzadeh dat CK-remming leidt tot een sterkere vaatverwijding dan andere middelen. Dit biedt wellicht een verklaring voor de hogere bloeddruk in deze groep.

Atherosclerose (aderverkalking) ontstaat door een ingewikkeld samenspel van risicofactoren en lokale omstandigheden in de bloedvaten. Hanke Matlung bestudeerde deze omstandigheden met experimentele modellen en menselijk weefsel. Zij vond relaties tussen het stromingsprofiel van het bloed, interactie van witte bloedcellen met de vaatwand, en het risico op atherosclerose en kwetsbare plaques. Een cruciale factor hierin was het enzym transglutaminase, dat een rol speelt in zowel de interactie van leukocyten met de vaatwand als in calcificatie. Dit biedt aanknopingspunten voor toekomstige behandeling.