Research Britt Opdebeeck

Abstract

Arterial media calcification (AMC) is defined as the accumulation of calcium-phosphate crystals in the medial layer of the arterial wall and is a major cardiovascular complication during aging and in patients with chronic kidney disease (CKD), diabetes and osteoporosis. AMC develops as a result of calcifying vascular smooth muscle cells (VSMC). Recently, however, the laboratory of Pathophysiology found strong evidence for the contribution of endothelial dysfunction (primarily characterized by reduced nitric oxide (NO) bioavailability) to AMC development. In this project, we will evaluate how endothelial cells (EC) can act as primary sensors of circulating triggers for AMC. We will use an in vitro EC/VSMC coculture model that will allow an in-depth investigation of the molecular effects of different calcification triggers on EC function, EC/VSMC interaction (with specific attention to NO signaling) and VSMC calcification. This detailed investigation of the endothelial phenotype during AMC could also potentially lead to the identification of new endothelial targets to treat AMC. Next, the therapeutic potential of restoring NO bioavailability in AMC will be preclinically evaluated in CKD and non-CKD induced AMC. In this way, we aim to contribute to the search for save, efficient arterial media calcification treatments, independent of patient population specific risk factors and not affecting bone health, as often seen with compounds that directly inhibit VSMC calcification.

Researcher(s)

• Promoter: Verhulst Anja
• Co-promoter: Opdebeeck Britt
• Fellow: Adriaensen Saar

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Arterial media calcification or the deposition of hydroxy-apatite (calcium-phosphate) crystals in the medial layer of the vessel wall occurs as a result of ageing and is accelerated in chronic kidney disease (CKD), diabetes and osteoporosis. Arterial media calcification has severe cardiovascular consequences including arterial stiffening, hypertension, impaired coronary perfusion, cardiac stroke and left ventricular hypertrophy, ultimately leading to heart failure. Consequently, this pathology has a high impact on patients' quality of live, economic activity and survival. Currently available therapies lack efficacy since they do not directly target the calcification process itself, however, act indirectly by controlling its risk factors. Furthermore, studies performed in the Laboratory of Pathophysiology repeatedly showed that compounds efficiently targeting arterial media calcification compromise physiological bone mineralization, which can be attributed to the fact that arterial media calcification resembles highly to physiological bone mineralization. This project aims to contribute to the search for save, efficient, arterial media calcification treatments, independent of patient population specific risk factors and not affecting bone health.

Researcher(s)

• Promoter: Verhulst Anja
• Co-promoter: Opdebeeck Britt
• Fellow: Adriaensen Saar

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Arterial media calcification is a severe cardiovascular complication in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. This disease is a master of camouflage by disguising itself as physiological bone mineralization, which makes it extremely difficult to find efficient and safe therapies against it, i.e. without affecting bone metabolism. The more as CKD and osteoporosis patients already suffer from bone mineralization defects. The candidate's FWO pre-doc project showed for the first time that the ATP analogue ?,?-meATP completely prevented all calcification in vascular smooth muscle cell cultures and efficiently prevented the development of arterial media calcification in rats, however also provoked deleterious effects on bone mineralization. Also other studies performed in the Laboratory of Pathophysiology showed repeatedly that compounds targeting arterial media calcification compromises physiological bone mineralization. Therefore, this FWO Post-doctoral junior project proposal focusses on developing a Poly(lactic-co-glycolic acid) (PGLA) nanoparticle conjugated to anti-elastin antibody drug delivery system to target ?,?-meATP selectively to the blood vessels, bypassing the bone compartment, and increase its bioavailability. PGLA nanoparticles have a high biocompatibility and biodegradability and are FDA approved for human therapy. The nanoparticles will be tested on in vitro and in vivo arterial calcification models.

Researcher(s)

• Promoter: Verhulst Anja
• Fellow: Opdebeeck Britt

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Arterial media calcification (AMC) is the deposition of calcium-phosphate crystals in the medial layer of the arterial wall and is an independent risk factor for cardiovascular morbidity/mortality. Efficient treatment for this lethal, highly prevalent pathology is lacking. Vascular smooth muscle cells, the key cell type in AMC, under oxidative stress transdifferentiate into cells with bone-forming capacity or die. It is not clear, however, which cell death type is most important. Ferroptosis, a recently discovered regulated type of cell death, is the result of iron-catalyzed, oxidative stress-induced membranous lipid peroxidation. Several arguments from literature and preliminary results from our lab put forward a role for iron accumulation, lipid peroxidation/ferroptosis in the process of AMC. This project aims to further substantiate this role by exploring the AMC-aggravating effect of iron in a chronic kidney disease (CKD) setting. Knowing this is crucial since CKD patients suffer from anaemia and thus routinely receive intravenous iron therapy. Moreover, the availability of in-house developed and patented ferroptosis inhibitors offers the unique opportunity to investigate their putative application and benefit in the clinical context of arterial media calcification. Hereto, we will preclinical test these inhibitors in a rat model for chronic kidney disease and arterial media calcification.

Researcher(s)

• Promoter: Opdebeeck Britt

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Vascular calcification or the deposition of calcium-phosphate crystals in the arteries has a severe impact on morbidity/mortality in elderly and patients with chronic kidney disease (CKD) and diabetes mellitus (DM) by inducing severe cardiovascular events. In our ageing society (CKD and DM are ageing diseases), treatment for vascular calcification is warranted. However, current therapies only consist of controlling risk factors and therefore effective therapies to prevent/cure vascular calcification are lacking. For this reason we aim to investigate new treatment strategies that directly inhibit arterial calcification in two ways (i) directly interfering with crystal formation in the vessel wall and (ii) directly targeting the predominant cells in arterial calcification; by targeting respectively cell receptor independent and dependent effects of extracellular nucleotides on the vascular calcification process. Treatments will not only be tested for their ability to prevent vascular calcifications but also to attenuate the progression of pre-existing calcifications as most patients present themselves with a given degree of vascular calcification. Since vascular calcification shares many features with the bone formation process it is furthermore important to test new therapies inhibiting vascular calcifications for negative effects on the bone. In conclusion, the aim of this project is to develop effective therapies for vascular calcification without side-effects on the bone

Researcher(s)

• Promoter: D'Haese Patrick
• Co-promoter: Neven Ellen
• Co-promoter: Verhulst Anja
• Fellow: Opdebeeck Britt

Research team(s)

• Pathophysiology

Project type(s)

• Research Project