Research Constantijn Franssen

Abstract

The Rodent Oscillatory Tension Setup to study Arterial Compliance (ROTSAC) is an advanced in-house developed system designed to measure vascular stiffness. It enables biomechanical analysis of vascular segments under physiological conditions, accurately replicating in vivo cyclic stretch, and has become a cornerstone of our research, facilitating numerous collaborations. Vascular stiffness is a critical factor in cardiovascular health and contributes to the progression of various diseases, including chronic kidney disease and Alzheimer's disease. Given its widespread impact, being able to accurately measure arterial stiffness in preclinical mouse models is essential for identifying drug targets and developing therapeutic strategies. The ROTSAC platform offers significant advantages over in vivo approaches to measure vascular stiffness, by providing precise control of loading conditions, replicating systolic and diastolic blood pressure, and isolating the arterial response for deeper insights into both passive and active arterial mechanics. Additionally, this platform replicates dynamic pulsatile conditions at 600 beats per minute, mimicking the cyclic stretch of mouse aortas, overcoming the limitations of static ex vivo systems that fail to reflect physiological conditions. However, after years of extensive use, critical components of the ROTSAC system have reached their operational limits, necessitating a comprehensive upgrade. The planned enhancements include replacing outdated force-length transducers and actuators, integrating new measurement amplifiers, and automating the system for greater efficiency. These upgrades will ensure precise, stable measurements, reduce measurement time, and increase sample throughput. By implementing these improvements, the ROTSAC will remain a state-of-the-art platform for vascular biomechanics research, advancing our understanding of arterial stiffness and supporting continued progress in vascular health research.

Researcher(s)

• Promoter: Roth Lynn
• Co-promoter: De Meyer Guido
• Co-promoter: Franssen Constantijn
• Co-promoter: Verhulst Stijn
• Co-promoter: Verstraeten Aline

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Recently, we discovered upregulation of a certain protein (SERPINA3) in a mouse model of chemotherapy-related cardiac dysfunction (CTRCD). This observation was confirmed by higher SERPINA3 plasma levels in patients with CTRCD. Growing evidence points to SERPINA3 as prognostic marker in cardiovascular disease, yet its role in cardiovascular pathology is poorly understood. The current proposal will shed light on the role of SERPINA3 in CTRCD, as well as its possible use as predictive marker. A bench to bedside approach will be implemented taking advantage of an established experimental mouse model of CTRCD induced by doxorubicin, combined with a prospective clinical trial in anthracycline-treated lymphoma patients. First, SERPINA3 knockout and wild type mice will be subjected to CTRCD to investigate the role of SERPINA3 in cardiac and vascular dysfunction. More specifically, the role of SERPINA3 on inflammatory pathways, as well as on ferroptosis will be evaluated. The in vivo study will be complemented with in vitro experiments with primary endothelial cells (EC), cardiomyocytes and vascular smooth muscle cells. A second part involves a translational in vivo study aimed to evaluate the effect of cardioprotective (heart failure, HF) drugs (i.e., an ACE-inhibitor+betablocker and an SGLT2-inhibitor) in the CTRCD mouse model with specific focus on SERPINA3 and EC-function. Finally, a third part involves a prospective, multicentric, observational study in lymphoma patients treated with anthracycline-based chemotherapy to investigate plasma SERPINA3 and retinal EC-function during CTRCD and its treatment with HF drugs. Ultimately, this project will contribute to the validation of SERPINA3 as predictive marker and will provide proof of concept of SERPINA3 as therapeutic strategy.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: Franssen Constantijn
• Fellow: De Wilde Leonie

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized oncological care, but cardiovascular immune related adverse events are feared. There is growing evidence suggesting that ICI accelerate atherosclerosis or even lead to increased risk for acute coronary syndromes. The current proposal studies the effects of ICI on the cardiovascular system, hypothesizing that ICI induce endothelial inflammation and dysfunction. VCAM-1 is expected to be key in these processes and could function as a potential target in future project proposals. Mice (C57/Bl6 and ApoE-/-) will be treated with ICI for one week and undergo in vivo functional cardiovascular assessment with echocardiography and pulse wave velocity. Upon sacrifice, ex vivo endothelial function will be studied and inflammatory markers will be analyzed. The purpose of this proposal is to demonstrate early endothelial inflammation and VCAM-1 upregulation after ICI treatment. This hypothesis was incorporated in previous grant proposals (FWO Junior Project, Stand up against Cancer, Foundation against Cancer) and was positively reviewed and considered relevant and novel, but preliminary data were absent. With this BOF Small Research Grant, preliminary data will be obtained to apply for further funding and start this new line of research within GENCOR.

Researcher(s)

• Promoter: Franssen Constantijn

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project