The integrity of the vascular wall is dependent on proper cell-cell contact between endothelial cells. This cell-cell contact is mediated by VE (Vascular Endothelial)-cadherin (CD144), a calcium-dependent homotypic adhesion molecule. The adhesive function of VE-cadherin is regulated in a dynamic fashion by both extracellular stimuli (VEGF, TNF, thrombin, as well as vessel wall stiffness, etc) and intracellular signalling. For the regulation of VE-cadherin, its link to the actin cytoskeleton, via its intracellular domain, is essential.
To increase our molecular insights in these events, our group focuses on the regulation of actin dynamics in the context of endothelial integrity.
In this line of research, we are particularly interested in the role and regulation of Rho-like GTPases. We use a range of in vitro approaches in combination with confocal microscopy and electrical resistance measurements of endothelial monolayers. More recently, we started detailed studies on the regulation of Rho GTPases by ubiquitylation.
Related research activities aim to link our molecular studies in endothelial cells to human disease. In collaboration with our colleagues from the clinic, we focus specifically on hypertensive disorders and cardiac disease related to diastolic dysfunction.
1. Dorland YL, Malinova TS, van Stalborch AM, Grieve AG, van Geemen D, Jansen NS, de Kreuk BJ, Nawaz K, Kole J, Geerts D, Musters RJ, de Rooij J, Hordijk PL, Huveneers S. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions. Nat Commun. 2016 Jul 15;7:12210.
2. Reinhard NR, van Helden SF, Anthony EC, Yin T, Wu YI, Goedhart J, Gadella TW, Hordijk PL. Spatiotemporal analysis of RhoA/B/C activation in primary human endothelial cells. Sci Rep. 2016 6:25502.
3. Huveneers S, Daemen MJ, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015 ;116(5):895-908.
4. van Geemen D, Smeets MW, van Stalborch AM, Woerdeman LA, Daemen MJ, HordijkPL, Huveneers S. F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries and veins. Arterioscler Thromb Vasc Biol. 2014 ;34(9):2059-67
5. Schaefer A, Te Riet J, Ritz K, Hoogenboezem M, Anthony EC, Mul FP, de Vries CJ, Daemen MJ, Figdor CG, van Buul JD, Hordijk PL. Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration. J Cell Sci. 2014;127(Pt 20):4470-82.
Jan van Bezu, technician
Igor Kovacevic, post-doc
Joana Amado de Azevedo
Anne de Leeuw