De Waard Lab

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Using en face immunofluorescence confocal microscopy, we showed that endothelial cell alignment with blood flow was reduced and junctional linearity was decreased in aortae of in Marfan mice (Fbn1C1041G/+). This modified phenotype was most prominent in the ascending aorta and occurred before aortic dilatation. To reverse the diseased endothelial morphology, we performed a 3 week treatment in Marfan mice with polyphenol resveratrol. This restored blood flow alignment, junctional linearity, phospho-eNOS expression at the cell membrane, and improved the structural integrity of the internal elastic lamina of the Marfan aorta.

Fiftyseven Marfan syndrome patients, aged 37±9 years, of which 28 males (49%) were included in the clinical trial (NL66127.018.18). Approximately half of them, 46% (26/57), had undergone aortic root replacement prior to the study, thus were studied for the remaining thoracic aorta. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (native root only; from 0.39±0.06 to -0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to -0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072). Thus, Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with Marfan syndrome. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with Marfan syndrome.

The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.

Myrthe Hoogeland

Biotechnician

Daan Bosshardt

PhD candidate

Philipp Hauger

PhD candidate

Tara van Merrienboer

PhD candidate

Shaynah Wanga

PhD candidate

Samira van Knippenberg

PhD candidate

De Waard Lab

Alumni