What we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The... Show moreWhat we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The stress response is for an important part dependent on glucocorticoid hormones. By and large, the acute response to glucocorticoids is beneficial, but chronic exposure often becomes maladaptive. To improve prevention and treatment of disorders we can develop due to stress, it is important to better understand the effects and working mechanisms of glucocorticoids. While we already possess extensive knowledge regarding glucocorticoids and glucocorticoid receptor signaling, we introduced and studied five “aspects of context”, which we felt address important current misconceptions or gaps of knowledge. Corticosterone was at the center of all the studies we performed, yet the eventual outcome of glucocorticoid receptor activation differed extensively in all experiments. Thus, the context in which corticosterone exerts its effects matters, and it is to researcher to be aware of this when designing new studies and interpreting available data. Whilst our research merely addressed some specific processes, the lessons learned from these experiments can be applied much broader to the biology of glucocorticoid signaling and other nuclear family members. Show less
BackgroundPatients with a bicuspid aortic valve (BAV) have an increased risk to develop aortic complications. Many studies are pointing towards a possible embryonic explanation for the development... Show moreBackgroundPatients with a bicuspid aortic valve (BAV) have an increased risk to develop aortic complications. Many studies are pointing towards a possible embryonic explanation for the development of both a bicuspid aortic valve as well as a defective ascending aortic wall in these patients. The fetal and newborn ascending aortic wall has however scarcely been studied in bicuspid aortic valve patients. We hypothesize that early histopathological defects might already be visible in the fetal and pediatric ascending aortic wall of bicuspid aortic valve patients, indicating at an early embryonic defect.MethodsNon-dilated BAV ascending aortic wall samples were collected (n = 40), categorized in five age groups: premature (age range 17.5 weeks + days GA till 37.6 weeks + days GA) 2. neonate (age range 1 – 21 days) 3. infant (age range 1 month – 4 years) 4. adolescent (age range 12 years – 15 years) and 5. adult (age range 41 – 72 years). Specimen were studied for intimal and medial histopathological features.ResultsThe premature ascending aortic wall has a significantly thicker intimal and significantly thinner medial layer as compared to all other age categories (p < 0.05). After birth the intimal thickness decreases significantly. The medial layer increases in thickness before adulthood (p < 0.05) with an increasing number of elastic lamellae (p < 0.01) and interlamellar mucoid extracellular matrix accumulation (p < 0.0001). Intimal atherosclerosis was scarce and medial histopathological features such as overall medial degeneration, smooth muscle cell nuclei loss and elastic fiber fragmentation were not appreciated in the BAV ascending aortic wall of any age.ConclusionsThe main characteristics of a bicuspid ascending aortic wall are already present before adulthood, albeit not before birth. Considering the early manifestations of ascending aortic wall pathology in bicuspid aortic valve patients, the pediatric population should be considered while searching for markers predictive for future aortopathy. Show less
A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac deformity, which is associated with an increased risk to develop a thoracic aortic aneurysm and/or an aortic dissection as... Show moreA bicuspid aortic valve (BAV) is the most prevalent congenital cardiac deformity, which is associated with an increased risk to develop a thoracic aortic aneurysm and/or an aortic dissection as compared to persons with a tricuspid aortic valve. Due to the high prevalence of a BAV in the general population and the associated life-long increased risk for adverse vascular events, BAV disease places a considerable burden on the public health. The aim of the present review is to discuss the role of transforming growth factor beta (TGF-ss) signaling in the development of the vascular wall and on how this complex signaling pathway may be involved in thoracic aortic aneurysm formation in tricuspid and BAV patients. Show less
Pluijm, I. van der; Burger, J.; Heijningen, P.M. van; Ijpma, A.; Vliet, N. van; Milanese, C.; ... ; Essers, J. 2018
Aim Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying... Show moreAim Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying aneurysm formation.Methods and results In Fibulin-4(R/R) mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on Fibulin-4(R/R) mouse aortas. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4(R/R) aortas. Consistently, functional studies in Fibulin-4(R/R) vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Yet, mitochondria in Fibulin-4(R/R) VSMCs showed no aberrant cytoplasmic localization. We found similar reduced mitochondrial respiration in Tgfbr-1(M318R/+) VSMCs, a mouse model for Loeys-Dietz syndrome (LDS). Interestingly, also human fibroblasts from Marfan (FBN1) and LDS (TGFBR2 and SMAD3) patients showed lower oxygen consumption. While individual mitochondrial Complexes I-V activities were unaltered in Fibulin-4(R/R) heart and muscle, these tissues showed similar decreased oxygen consumption. Furthermore, aortas of aneurysmal Fibulin-4(R/R) mice displayed increased reactive oxygen species (ROS) levels. Consistent with these findings, gene expression analyses revealed dysregulation of metabolic pathways. Accordingly, blood ketone levels of Fibulin-4(R/R) mice were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. As predicted by gene expression analysis, the activity of PGC1 alpha, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4(R/R) VSMCs. Increased TGF beta reduced PGC1 alpha levels, indicating involvement of TGF beta signalling in PGC1 alpha regulation. Activation of PGC1 alpha restored the decreased oxygen consumption in Fibulin-4(R/R) VSMCs and improved their reduced growth potential, emphasizing the importance of this key regulator.Conclusion Our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation. Show less
Pluijm, I. van der; Burger, J.; Heijningen, P.M. van; Ijpma, A.; Vliet, N. van; Milanese, C.; ... ; Essers, J. 2018
DNA-based human identification is employed in varying situations, such as disaster victim identification, relationship testing and forensic analyses. When DNA is of low quality and/or quantity,... Show moreDNA-based human identification is employed in varying situations, such as disaster victim identification, relationship testing and forensic analyses. When DNA is of low quality and/or quantity, standard methods for DNA profiling may not suffice. The research described in this thesis is aimed at the development of additional or alternative methods to extract information from a person__s DNA. The explored methods include: optimised sampling, the use of smaller and/or other types of DNA markers, increased analysis sensitivity, DNA repair, and combining marker sets. These studies have been performed to get closer to the answer regarding the question: __To whom belongs this body?__ Show less
