Ploingarm Petsophonsakul (ESR 11) -  Nutraceuticals modulating the vascular vitamin K-system

A great deal of scientific literature to date has been devoted to describing cardiovascular disease (CVD) associated with endothelial dysfunction, lipid infiltration, and inflammation. However, very little is known about how vascular smooth muscle cells (VSMCs) influence CVD. VSMCs are the major cell type found in the vessel wall. They are essential for good performance of the vasculature and maintain appropriate blood flow. VSMCs are also involved in many vascular diseases such as atherosclerosis and aneurysm formation. In these pathologies, VSMCs play important role in remodeling of the vessel wall. A contractile VSMC can switch its phenotype to become synthetic and express abundant vesicle proteins which then further mediate vascular remodeling. VSMC synthesized vitamin K dependent protein (VKDP) which regulates VSMC phenotypic switching called matrix Gla protein (MGP). MGP maintains the contractile phenotype of VSMC and support vascular elasticity. MGP binds to BMP-2 and inhibits downstream regulation of VSMC switching towards osteochondrogenic phenotype which induces calcification. It also prevents mineralization of vesicles produced by VSMCs.

Vitamin K2 supports cardiovascular health by activating VSMC derived MGP to inhibit phenotypic switching and vascular calcification. In addition, vitamin K2 has also an effect on non-canonical pathways such as inhibition of oxidative stress and supporting ATP synthesis.

I am particularly interested in the vitamin K metabolism in aneurysm. Aneurysm is an enlargement of the artery caused by weakness in the aortic wall. It is characterized by pronounced oxidative stress, VSMC phenotypic switching and VSMC apoptosis. Thus, leading to extracellular matrix (ECM) degradation and weakening of the arterial vessel wall. Moreover, aortic stiffening and/or calcification generates aortic wall stress which potentially accelerates the dilatation of the vessel wall and thereby contribute to aneurysm growth. The sequential pathophysiology of aneurysm formation is unclear, however VSMCs have increasingly been recognized as an important contributor to the disease.

The goal of this project is to optimize vascular homeostasis by vitamin K-analogues, specifically in prevention and treatment of vascular calcification by harnessing the protective endogenous vitamin K cycle of VSMC. The research project will focus on vitamin K metabolism in VSMC related to aneurysm formation. I will investigate the role of vitamin K-dependent mechanisms in VSMC, in particular related to oxidative stress, metabolic activity, phenotypic switching, senescence, and apoptosis.

My research approach includes both in vitro and in vivo studies. Human primary VSMCs from healthy donors and from patients suffering from aneurysms will be used for in vitro analysis. In preclinical experiments, animal models of vascular remodeling, apoptosis and calcification in relation to aneurysm formation will be used. Our animal models include apoE:sm22hDTr KI mice (VSMC apoptosis), smtn-/- mice (vascular remodeling), and warfarin diets (calcification). In addition, Human tissue, plasma and serum samples from the biobank of aneurysm patients at Maastricht UMC+ will be accessed. These human samples will allow us to investigate the pathologies of disease at the histological level.